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Nateghi-Rostami M, Lipoldová M, Sohrabi Y. Improving reproducibility and translational potential of mouse models: lessons from studying leishmaniasis. Front Immunol 2025; 16:1559907. [PMID: 40330482 PMCID: PMC12052738 DOI: 10.3389/fimmu.2025.1559907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 03/24/2025] [Indexed: 05/08/2025] Open
Abstract
Leishmaniasis is a complex disease caused by protozoan parasites of the genus Leishmania, which are transmitted by phlebotomine sand flies. The clinical manifestations of leishmaniasis are diverse, ranging from self-healing cutaneous lesions to fatal systemic disease. Mouse models are instrumental in advancing our understanding of the immune system against infections, yet their limitations in translating findings to humans are increasingly highlighted. The success rate of translating data from mice to humans remains low, largely due to the complexity of diseases and the numerous factors that influence the disease outcomes. Therefore, for the effective translation of data from murine models of leishmaniasis, it is essential to align experimental conditions with those relevant to human infection. Factors such as parasite characteristics, vector-derived components, host status, and environmental conditions must be carefully considered and adapted to enhance the translational relevance of mouse data. These parameters are potentially modifiable and should be carefully integrated into the design and interpretation of experimental procedures in Leishmania studies. In the current paper, we review the challenges and perspective of using mouse as a model for leishmaniasis. We have particularly emphasized the non-genetic factors that influence experiments and focused on strategies to improve translational value of studies on leishmaniasis using mouse models.
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Affiliation(s)
| | - Marie Lipoldová
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia
- Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czechia
| | - Yahya Sohrabi
- Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czechia
- Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czechia
- Department of Cardiology I-Coronary and Peripheral Vascular Disease, Heart Failure, University Hospital Münster, University of Münster, Münster, Germany
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Kay EJ, Zanivan S. The tumor microenvironment is an ecosystem sustained by metabolic interactions. Cell Rep 2025; 44:115432. [PMID: 40088447 DOI: 10.1016/j.celrep.2025.115432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 12/09/2024] [Accepted: 02/24/2025] [Indexed: 03/17/2025] Open
Abstract
Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up new avenues and create challenges for metabolically targeting the TME to hamper tumor growth and improve response to therapy. This perspective explores ways in which the CAF and immune components of the TME could metabolically influence each other, based on current knowledge of their metabolic states, interactions, and subpopulations.
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Affiliation(s)
- Emily Jane Kay
- Cancer Research UK Scotland Institute, Glasgow G61 1BD, UK.
| | - Sara Zanivan
- Cancer Research UK Scotland Institute, Glasgow G61 1BD, UK; School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK; Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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3
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Goto Y. Immunomodulation by Leishmania parasites: Potential for controlling other diseases. Parasitol Int 2025; 104:102987. [PMID: 39515578 DOI: 10.1016/j.parint.2024.102987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/01/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024]
Abstract
In the mammalian hosts, Leishmania parasites survive and proliferate within phagolysosomes of macrophages. To avoid being killed by the immune cells, Leishmania parasites utilize their molecules to manipulate macrophages' functions for survival. Targets of such immunomodulatory molecules are not limited to macrophages, as Leishmania-derived molecules sometimes show influence on other immune cells such as neutrophils, dendritic cells, T cells and B cells. This review covers research on immunomodulation of host immunity by Leishmania parasites and introduces some examples of parasite-derived molecules participating in the immunomodulation. For example, Leishmania cell surface lipophosphoglycan (LPG) can modulate TLR2 signaling and PI3K/Akt axis in macrophages leading to induction of Th2 cells. Because chronic secretion of inflammatory cytokines is one of the causes of immune-mediated diseases such as atherosclerosis, Crohn's disease, and rheumatoid arthritis, LPG may be useful as a drug to suppress the inflammatory conditions. The unique characteristics of leishmanial molecules pose a promise as a source of immunomodulatory drugs for controlling diseases other than leishmaniasis.
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Affiliation(s)
- Yasuyuki Goto
- Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Japan.
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Villadangos L, Serrador JM. Subcellular Localization Guides eNOS Function. Int J Mol Sci 2024; 25:13402. [PMID: 39769167 PMCID: PMC11678294 DOI: 10.3390/ijms252413402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/03/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Nitric oxide synthases (NOS) are enzymes responsible for the cellular production of nitric oxide (NO), a highly reactive signaling molecule involved in important physiological and pathological processes. Given its remarkable capacity to diffuse across membranes, NO cannot be stored inside cells and thus requires multiple controlling mechanisms to regulate its biological functions. In particular, the regulation of endothelial nitric oxide synthase (eNOS) activity has been shown to be crucial in vascular homeostasis, primarily affecting cardiovascular disease and other pathophysiological processes of importance for human health. Among other factors, the subcellular localization of eNOS plays an important role in regulating its enzymatic activity and the bioavailability of NO. The aim of this review is to summarize pioneering studies and more recent publications, unveiling some of the factors that influence the subcellular compartmentalization of eNOS and discussing their functional implications in health and disease.
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Affiliation(s)
| | - Juan M. Serrador
- Interactions with the Environment Program, Immune System Development and Function Unit, Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas (CSIC)—Universidad Autónoma de Madrid, 28049 Madrid, Spain;
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Ji M, Ran X, Zuo H, Zhang Q. Novel Insights into the Kallikrein-Kinin System in Fulminant Myocarditis: Physiological Basis and Potential Therapeutic Advances. J Inflamm Res 2024; 17:7347-7360. [PMID: 39429854 PMCID: PMC11490248 DOI: 10.2147/jir.s488237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/08/2024] [Indexed: 10/22/2024] Open
Abstract
Fulminant myocarditis (FM) is characterized by rapid cardiac deterioration often instigated by an inflammatory cytokine storm. The kallikrein-kinin system (KKS) is a metabolic cascade known for releasing vasoactive kinins, such as bradykinin-related peptides, possessing diverse pharmacological activities that include inflammation, regulation of vascular permeability, endothelial barrier dysfunction, and blood pressure modulation. The type 1 and type 2 bradykinin receptors (B1R and B2R), integral components of the KKS system, mediate the primary biological effects of kinin peptides. This review aims to offer a comprehensive overview of the primary mechanisms of the KKS in FM, including an examination of the structural components, regulatory activation, and downstream signaling pathways of the KKS. Furthermore, it explores the involvement of the tissue kallikrein/B1R/inducible nitric oxide synthase (TK/B1R/iNOS) pathway in myocyte dysfunction, modulation of the immune response, and preservation of endothelial barrier integrity. The potential therapeutic advances targeting the inhibition of the KKS in managing FM will be discussed, providing valuable insights for the development of clinical treatment strategies.
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Affiliation(s)
- Mengmeng Ji
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Xiao Ran
- Department of Critical-Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Houjuan Zuo
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
| | - Qin Zhang
- Department of Anesthesiology, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China
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Wilkins-Rodríguez AA, Salazar-Schettino PM, Manning-Cela RG, Gutiérrez-Kobeh L. Differential Regulation of L-Arginine Metabolism through NOS2 and Arginases during Infection with Trypanosoma cruzi. Pathogens 2024; 13:878. [PMID: 39452749 PMCID: PMC11510043 DOI: 10.3390/pathogens13100878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/28/2024] [Accepted: 09/30/2024] [Indexed: 10/26/2024] Open
Abstract
L-arginine metabolism through arginases and inducible nitric oxide synthase (NOS2) constitutes a fundamental axis for the resolution or progression of Chagas disease. Infection with Trypanosoma cruzi can cause a wide spectrum of disease, ranging from acute forms contained by the host immune response to chronic ones, such as the chronic chagasic cardiomyopathy. Here, we analyzed, in an in vitro model, the ability of two T. cruzi isolates, with different degrees of virulence, to regulate the metabolism of L-arginine through arginase 1 (Arg-1) and NOS2 in macrophages and through arginase 2 (Arg-2) and NOS2 in cardiomyocytes. Stimulation of bone marrow-derived macrophages (BMMΦ), obtained from CD1 mice, with TNF-α + IFN-γ induced their polarization into classically activated macrophages (CAMΦ), which expressed functional NOS2, while stimulation with IL-4 induced their polarization into alternatively activated macrophages (AAMΦ), which expressed functional Arg-1. Interestingly, stimulation of cardiomyocytes, obtained from hearts of CD1 neonatal mice, with TNF-α + IFN-γ or IL-4 also resulted in functional NOS2 and arginase expression, as observed in CAMΦ and AAMΦ, but Arg-2 was the arginase isoform expressed instead of Arg-1. We observed that infection of BMMΦ with the more virulent T. cruzi isolate (QRO) importantly diminished NOS2 expression and nitric oxide (NO) production in CAMΦ, allowing parasite survival, while infection with the less virulent isolate (CI2) did not diminish NOS2 activity and NO production in CAMΦ to a great extent, which resulted in parasite killing. Regarding Arg-1, infection of BMMΦ with the QRO isolate significantly induced Arg-1 expression and activity in AAMΦ, which resulted in a higher parasite load than the one in the unstimulated BMMΦ. Even though infection with CI2 isolate did not increase Arg-1 expression and activity in AAMΦ, the parasite load was higher than the one in the unstimulated BMMΦ but at a lesser magnitude than that observed during infection with the QRO isolate. On the other hand, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with TNF-α + IFN-γ inhibited NOS2 expression and NO production, leading to amelioration of infection. Surprisingly, infection of cardiomyocytes with either QRO or CI2 isolates and further stimulation with IL-4 strongly inhibited Arg-2 expression and function, which resulted in parasite loads similar to those observed in unstimulated cardiomyocytes. Our results suggest that T. cruzi isolates that exhibit variable virulence or pathogenicity degrees differentially regulate L-arginine metabolism through Arg-1/2 and NOS2 in macrophages and cardiomyocytes.
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Affiliation(s)
- Arturo A. Wilkins-Rodríguez
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México-Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico;
| | - Paz María Salazar-Schettino
- Laboratorio de Biología de Parásitos, Departamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Rebeca G. Manning-Cela
- Departamento de Biomedicina Molecular, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City 07360, Mexico;
| | - Laila Gutiérrez-Kobeh
- Unidad de Investigación UNAM-INC, División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México-Instituto Nacional de Cardiología “Ignacio Chávez”, Mexico City 14080, Mexico;
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Heidari-Kharaji M, Guerra SS, Puneiad RP. Effects of Amphotericin B-Conjugated Functionalized Carbon Nanoparticles in the Treatment of Cutaneous Leishmaniasis. Parasite Immunol 2024; 46:e13068. [PMID: 39363635 DOI: 10.1111/pim.13068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/04/2024] [Accepted: 09/21/2024] [Indexed: 10/05/2024]
Abstract
Leishmaniasis is a parasitic disease spread by the bite of an infected sandfly and caused by protozoan parasites of the genus Leishmania. Currently, there is no vaccine available for leishmaniasis in humans, and the existing chemotherapy methods face various clinical challenges. The majority of drugs are limited to a few toxic compounds, with some parasite strains developing resistance. Therefore, the discovery and development of a new anti-leishmanial compound is crucial. One promising strategy involves the use of nanoparticle delivery systems to accelerate the effectiveness of existing treatments. In this study, Amphotericin B (AmB) was incorporated into functionalized carbon nanotube (f-CNT) and evaluated for its efficacy against Leishmania major in vitro and in a BALB/c mice model. The increase in footpad thickness was measured, and real-time PCR was used to quantify the parasite load post-infection. Levels of nitric oxide and cytokines IL-4 and IFN-γ were also determined. We found that f-CNT-AmB significantly reduced the levels of promastigotes and amastigotes of the Leishmania parasite. The nanoparticle showed strong anti-leishmanial activity with an IC50 of 0.00494 ± 0.00095 mg/mL for promastigotes and EC50 of 0.00294 ± 0.00065 mg/mL for amastigotes at 72 h post-infection, without causing harm to mice macrophages. Treatment of infected BALB/c mice with f-CNT-AmB resulted in a significant decrease in cutaneous leishmania (CL) lesion size in the foot pad, as well as reduced Leishmania burden in both lymph nodes and spleen. The levels of nitric oxide and IFN-γ significantly increased in the f-CNT-AmB treated groups. Also, our results showed that the level of IL-4 significantly decreased after f-CNT-AmB treatment in comparison to other groups. In conclusion, our results demonstrate that AmB loaded into f-CNT is significantly more effective than AmB alone in inhibiting parasite propagation and promoting a shift towards a Th1 response.
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Affiliation(s)
- Maryam Heidari-Kharaji
- Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri, USA
- Skin and Stem Cell Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Liccardo D, Valletta A, Spagnuolo G, Vinciguerra C, Lauria MR, Perrotta A, Del Giudice C, De Luca F, Rengo G, Rengo S, Rengo C, Cannavo A. Porphyromonas gingivalis virulence factors induce toxic effects in SH-SY5Y neuroblastoma cells: GRK5 modulation as a protective strategy. J Biotechnol 2024; 393:7-16. [PMID: 39033880 DOI: 10.1016/j.jbiotec.2024.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 07/02/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024]
Abstract
Periodontitis (PDS) is a chronic inflammatory disease initiated by a dysbiosis of oral pathogenic bacterial species, such as Porphyromonas gingivalis (Pg). These bacteria can penetrate the bloodstream, releasing various endo and exotoxins that fuel the infection, and stimulate toxic inflammation in different compartments, including the brain. However, the specific mechanisms by which PDS/Pg contribute to brain disorders, such as Alzheimer's disease (AD), remain unclear. This study assessed the effects of Pg's virulence factors - lipopolysaccharide (LPS-Pg) and gingipains (gps) K (Kgp) and Rgp - on SH-SY5Y cells. Our results demonstrated that LPS-Pg activated signaling through the Toll-like receptor (TLR)-2/4 induced a significant downregulation of G protein-coupled receptor kinase 5 (GRK5). Additionally, LPS-Pg stimulation resulted in a robust increase in Tau phosphorylation (pTau) and p53 levels, while causing a marked reduction in Bcl2 and increased cell death compared to unstimulated cells (Ns). LPS-Pg also elevated inducible nitric oxide synthase (iNOS) expression, leading to oxidative damage. In cells overexpressing GRK5 via Adenovirus, LPS-Pg failed to increase iNOS and pTau levels compared to GFP control cells. High GRK5 levels also prevented the nuclear accumulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, the overexpression of a GRK5 mutant form lacking the nuclear localization signal (ΔNLS) nearly abolished LPS-Pg induced p53 and iNOS upregulation. Finally, we tested whether Kgp and Rgp mediated similar effects and our data showed that both gps caused a marked downregulation of GRK5 leading to increased p53 and pTau levels. In conclusion, this study provides further insight into the toxic effects elicited by Pg in cells and suggests that preventing GRK5 deficiency may be a valid strategy to mitigate Pg-induced toxic effects (i.e. cell death, oxidative damage, and Tau hyperphosphorylation) in SH-SY5Y cells, which are typical molecular hallmarks of neurodegenerative disorders.
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Affiliation(s)
- Daniela Liccardo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Alessandra Valletta
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Gianrico Spagnuolo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Caterina Vinciguerra
- Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Maria Rosaria Lauria
- Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Alessia Perrotta
- Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Carmela Del Giudice
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Francesca De Luca
- Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Giuseppe Rengo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy; Istituti Clinici Scientifici Maugeri IRCCS - Scientific Institute of Telese Terme (BN), Italy
| | - Sandro Rengo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples 80131, Italy
| | - Carlo Rengo
- Dental School of Periodontology, University of Naples Federico II, Napoli 80127, Italy.
| | - Alessandro Cannavo
- Department of Translational Medical Sciences, University of Naples Federico II, Naples 80131, Italy.
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Diel KAP, Santana Filho PC, Pitol Silveira P, Ribeiro RL, Teixeira PC, Rodrigues Júnior LC, Marinho LC, Romão PRT, von Poser GL. Antiprotozoal potential of Vismia species (Hypericaceae), medicinal plants used to fight cutaneous leishmaniasis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 328:118028. [PMID: 38492792 DOI: 10.1016/j.jep.2024.118028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/26/2024] [Accepted: 03/07/2024] [Indexed: 03/18/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Species of Vismia (Hypericaceae), known in Brazil as "lacre", are commonly used in traditional Amazonian medicine for the treatment of skin lesions, including those caused by Leishmania infection. AIM OF THE STUDY Hexane extracts from the leaves of Vismia cayennensis, V. gracilis, V. sandwithii and V. guianensis, as well as from the fruits of the latter, in addition to the anthraquinones vismiaquinone, physcion and chrysophanol isolated from these species were explored for their anti-promastigote and anti-amastigote activity on Leishmania amazonensis. MATERIALS AND METHODS Extracts were prepared by static maceration with n-hexane. The compounds, isolated by chromatographic techniques, were identified by spectroscopic methods (1H and 13C NMR). Promastigotes of L.amazonensis were incubated with hexane extracts (1-50 μg/mL) or anthraquinones (1-50 μM) and the parasite survival analyzed. The action of compounds on reactive oxygen species (ROS) production, mitochondrial membrane potential, and membrane integrity of promastigotes were evaluated by flow cytometer, and the cytotoxicity on mammalian cells using MTT assay. Furthermore, the activity of compounds against amastigotes and nitric oxide production were also investigated. RESULTS Vismiaquinone and physcion were obtained from the leaves of V. guianensis. Physcion, as well as chrysophanol, were isolated from V. sandwithii. Vismia cayennensis and V. gracilis also showed vismiaquinone, compound detected in lower quantity in the fruits of V. guianensis. All extracts were active against the parasite, corroborating the popular use. The greatest activity against promastigotes was achieved with V. guianensis extract (IC50 4.3 μg/mL), precisely the most used Vismia species for treating cutaneous leishmaniasis. Vismiaquinone and physcion exhibited relevant activity with IC50 12.6 and 2.6 μM, respectively. Moreover, all extracts and anthraquinones tested induced ROS production, mitochondrial dysfunction, membrane disruption and were able to kill intracellular amastigote forms, being worthy of further in vivo studies as potential antileishmanial drugs. CONCLUSIONS The overall data achieved in the current investigation scientifically validate the traditional use of Vismia species, mainly V. guianensis, as an anti-Leishmania agent. Furthermore, the promising results presented here indicate species of Vismia as potentially useful resources of Brazilian flora for the discovery of therapeutic solutions for neglected diseases.
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Affiliation(s)
- Kriptsan Abdon Poletto Diel
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação em Ciências Farmacêuticas, Avenida Ipiranga 2752, Santana, 90610-000, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paulo Cesar Santana Filho
- Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Ciências Básicas da Saúde, Rua Sarmento Leite 245, Centro Histórico, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Pablo Pitol Silveira
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação em Ciências Farmacêuticas, Avenida Ipiranga 2752, Santana, 90610-000, Porto Alegre, Rio Grande do Sul, Brazil
| | - Rafaela Laura Ribeiro
- Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Ciências Básicas da Saúde, Rua Sarmento Leite 245, Centro Histórico, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Paula Coelho Teixeira
- Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Ciências Básicas da Saúde, Rua Sarmento Leite 245, Centro Histórico, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Luiz Carlos Rodrigues Júnior
- Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Ciências Básicas da Saúde, Rua Sarmento Leite 245, Centro Histórico, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil
| | - Lucas C Marinho
- Universidade Federal do Maranhão, Departamento de Biologia, Avenida dos Portugueses 1966, Bacanga, 65080-805, São Luís, Maranhão, Brazil
| | - Pedro Roosevelt Torres Romão
- Universidade Federal de Ciências da Saúde de Porto Alegre, Departamento de Ciências Básicas da Saúde, Rua Sarmento Leite 245, Centro Histórico, 90050-170, Porto Alegre, Rio Grande do Sul, Brazil.
| | - Gilsane Lino von Poser
- Universidade Federal do Rio Grande do Sul, Programa de Pós-Graduação em Ciências Farmacêuticas, Avenida Ipiranga 2752, Santana, 90610-000, Porto Alegre, Rio Grande do Sul, Brazil.
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Wu HM, Yang YV, Huang NJ, Fan LP, Dai YY, Hu KT, Tang TY, Liu L, Xu Y, Liu DT, Cai ZX, Niu XY, Ren XY, Yao ZH, Qin HY, Chen JZ, Huang X, Zhang C, You X, Wang C, He Y, Hong W, Sun YX, Zhan YH, Lin SY. Probucol mitigates high-fat diet-induced cognitive and social impairments by regulating brain redox and insulin resistance. Front Neurosci 2024; 18:1368552. [PMID: 38716255 PMCID: PMC11074470 DOI: 10.3389/fnins.2024.1368552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/04/2024] [Indexed: 01/03/2025] Open
Abstract
Probucol has been utilized as a cholesterol-lowering drug with antioxidative properties. However, the impact and fundamental mechanisms of probucol in obesity-related cognitive decline are unclear. In this study, male C57BL/6J mice were allocated to a normal chow diet (NCD) group or a high-fat diet (HFD) group, followed by administration of probucol to half of the mice on the HFD regimen. Subsequently, the mice were subjected to a series of behavioral assessments, alongside the measurement of metabolic and redox parameters. Notably, probucol treatment effectively alleviates cognitive and social impairments induced by HFD in mice, while exhibiting no discernible influence on mood-related behaviors. Notably, the beneficial effects of probucol arise independently of rectifying obesity or restoring systemic glucose and lipid homeostasis, as evidenced by the lack of changes in body weight, serum cholesterol levels, blood glucose, hyperinsulinemia, systemic insulin resistance, and oxidative stress. Instead, probucol could regulate the levels of nitric oxide and superoxide-generating proteins, and it could specifically alleviate HFD-induced hippocampal insulin resistance. These findings shed light on the potential role of probucol in modulating obesity-related cognitive decline and urge reevaluation of the underlying mechanisms by which probucol exerts its beneficial effects.
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Affiliation(s)
- Han-Ming Wu
- Department of Neurology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Yang Vivian Yang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Na-Jun Huang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Li-Ping Fan
- Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Ying-Ying Dai
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Ke-Ting Hu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Tian-Yu Tang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Lin Liu
- The Third Clinical Medical College, Fujian Medical University, Fuzhou, China
| | - Yue Xu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Dong-Tai Liu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Ze-Xin Cai
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Xiao-Yu Niu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Xin-Yi Ren
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Zheng-Hao Yao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Hao-Yu Qin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Jian-Zhen Chen
- Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Xi Huang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Cixiong Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Xiang You
- School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Chen Wang
- Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Ying He
- Laboratory Animal Center, Xiamen University, Xiamen, China
| | - Wei Hong
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
| | - Yu-Xia Sun
- Institute of Metabolism and Health, Henan University, Zhengzhou, China
| | - Yi-Hong Zhan
- Department of Neurology and Department of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Shu-Yong Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
- Department of Digestive Diseases, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China
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11
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Coavoy-Sanchez SA, da Costa Marques LA, Costa SKP, Muscara MN. Role of Gasotransmitters in Inflammatory Edema. Antioxid Redox Signal 2024; 40:272-291. [PMID: 36974358 DOI: 10.1089/ars.2022.0089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
Significance: Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are, to date, the identified members of the gasotransmitter family, which consists of gaseous signaling molecules that play central roles in the regulation of a wide variety of physiological and pathophysiological processes, including inflammatory edema. Recent Advances: Recent studies show the potential anti-inflammatory and antiedematogenic effects of NO-, CO-, and H2S-donors in vivo. In general, it has been observed that the therapeutical effects of NO-donors are more relevant when administered at low doses at the onset of the inflammatory process. Regarding CO-donors, their antiedematogenic effects are mainly associated with inhibition of proinflammatory mediators (such as inducible NO synthase [iNOS]-derived NO), and the observed protective effects of H2S-donors seem to be mediated by reducing some proinflammatory enzyme activities. Critical Issues: The most recent investigations focus on the interactions among the gasotransmitters under different pathophysiological conditions. However, the biochemical/pharmacological nature of these interactions is neither general nor fully understood, although specifically dependent on the site where the inflammatory edema occurs. Future Directions: Considering the nature of the involved mechanisms, a deeper knowledge of the interactions among the gasotransmitters is mandatory. In addition, the development of new pharmacological tools, either donors or synthesis inhibitors of the three gasotransmitters, will certainly aid the basic investigations and open new strategies for the therapeutic treatment of inflammatory edema. Antioxid. Redox Signal. 40, 272-291.
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Affiliation(s)
| | | | - Soraia Katia Pereira Costa
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Marcelo Nicolas Muscara
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
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12
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Milovic A, Duong JV, Barbour AG. The infection-tolerant white-footed deermouse tempers interferon responses to endotoxin in comparison to the mouse and rat. eLife 2024; 12:RP90135. [PMID: 38193896 PMCID: PMC10945503 DOI: 10.7554/elife.90135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024] Open
Abstract
The white-footed deermouse Peromyscus leucopus, a long-lived rodent, is a key reservoir in North America for agents of several zoonoses, including Lyme disease, babesiosis, anaplasmosis, and a viral encephalitis. While persistently infected, this deermouse is without apparent disability or diminished fitness. For a model for inflammation elicited by various pathogens, the endotoxin lipopolysaccharide (LPS) was used to compare genome-wide transcription in blood by P. leucopus, Mus musculus, and Rattus norvegicus and adjusted for white cell concentrations. Deermice were distinguished from the mice and rats by LPS response profiles consistent with non-classical monocytes and alternatively-activated macrophages. LPS-treated P. leucopus, in contrast to mice and rats, also displayed little transcription of interferon-gamma and lower magnitude fold-changes in type 1 interferon-stimulated genes. These characteristics of P. leucopus were also noted in a Borrelia hermsii infection model. The phenomenon was associated with comparatively reduced transcription of endogenous retrovirus sequences and cytoplasmic pattern recognition receptors in the deermice. The results reveal a mechanism for infection tolerance in this species and perhaps other animal reservoirs for agents of human disease.
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Affiliation(s)
- Ana Milovic
- Department of Microbiology & Molecular Genetics, University of California, IrvineIrvineUnited States
| | - Jonathan V Duong
- Department of Microbiology & Molecular Genetics, University of California, IrvineIrvineUnited States
| | - Alan G Barbour
- Departments of Medicine, Microbiology & Molecular Genetics, and Ecology & Evolutionary Biology, University of California, IrvineIrvineUnited States
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13
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Kapnick SM, Martin CA, Jewell CM. Engineering metabolism to modulate immunity. Adv Drug Deliv Rev 2024; 204:115122. [PMID: 37935318 PMCID: PMC10843796 DOI: 10.1016/j.addr.2023.115122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 07/19/2023] [Accepted: 10/25/2023] [Indexed: 11/09/2023]
Abstract
Metabolic programming and reprogramming have emerged as pivotal mechanisms for altering immune cell function. Thus, immunometabolism has become an attractive target area for treatment of immune-mediated disorders. Nonetheless, many hurdles to delivering metabolic cues persist. In this review, we consider how biomaterials are poised to transform manipulation of immune cell metabolism through integrated control of metabolic configurations to affect outcomes in autoimmunity, regeneration, transplant, and cancer. We emphasize the features of nanoparticles and other biomaterials that permit delivery of metabolic cues to the intracellular compartment of immune cells, or strategies for altering signals in the extracellular space. We then provide perspectives on the potential for reciprocal regulation of immunometabolism by the physical properties of materials themselves. Lastly, opportunities for clinical translation are highlighted. This discussion contributes to our understanding of immunometabolism, biomaterials-based strategies for altering metabolic configurations in immune cells, and emerging concepts in this evolving field.
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Affiliation(s)
- Senta M Kapnick
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, USA; Department of Veterans Affairs, VA Maryland Health Care System, 10 N Green Street, Baltimore, MD, USA
| | - Corinne A Martin
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, USA
| | - Christopher M Jewell
- Fischell Department of Bioengineering, University of Maryland, 8278 Paint Branch Drive, College Park, MD, USA; Department of Veterans Affairs, VA Maryland Health Care System, 10 N Green Street, Baltimore, MD, USA; Robert E. Fischell Institute for Biomedical Devices, 8278 Paint Branch Drive, College Park, MD, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, 22 S Greene Street, Suite N9E17, Baltimore, MD, USA.
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14
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Milovic A, Duong JV, Barbour AG. The white-footed deermouse, an infection-tolerant reservoir for several zoonotic agents, tempers interferon responses to endotoxin in comparison to the mouse and rat. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.06.543964. [PMID: 37745581 PMCID: PMC10515768 DOI: 10.1101/2023.06.06.543964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
The white-footed deermouse Peromyscus leucopus, a long-lived rodent, is a key reservoir for agents of several zoonoses, including Lyme disease. While persistently infected, this deermouse is without apparent disability or diminished fitness. For a model for inflammation elicited by various pathogens, the endotoxin lipopolysaccharide (LPS) was used to compare genome-wide transcription in blood by P. leucopus, Mus musculus and Rattus norvegicus and adjusted for white cell concentrations. Deermice were distinguished from the mice and rats by LPS response profiles consistent with non-classical monocytes and alternatively-activated macrophages. LPS-treated P. leucopus, in contrast to mice and rats, also displayed little transcription of interferon-gamma and lower magnitude fold-changes in type 1 interferon-stimulated genes. This was associated with comparatively reduced transcription of endogenous retrovirus sequences and cytoplasmic pattern recognition receptors in the deermice. The results reveal a mechanism for infection tolerance in this species and perhaps other animal reservoirs for agents of human disease.
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Affiliation(s)
- Ana Milovic
- Department of Microbiology & Molecular Genetics, University of California Irvine
| | - Jonathan V. Duong
- Department of Microbiology & Molecular Genetics, University of California Irvine
| | - Alan G. Barbour
- Departments of Medicine, Microbiology & Molecular Genetics, and Ecology & Evolutionary Biology, University of California Irvine
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15
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Leite-Silva J, Oliveira-Ribeiro C, Morgado FN, Pimentel MIF, Lyra MR, Fagundes A, Miranda LFC, Valete-Rosalino CM, Schubach AO, Conceição-Silva F. Is There Any Difference in the In Situ Immune Response in Active Localized Cutaneous Leishmaniasis That Respond Well or Poorly to Meglumine Antimoniate Treatment or Spontaneously Heal? Microorganisms 2023; 11:1631. [PMID: 37512804 PMCID: PMC10384164 DOI: 10.3390/microorganisms11071631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/26/2023] [Accepted: 04/27/2023] [Indexed: 07/30/2023] Open
Abstract
Localized cutaneous leishmaniasis caused by Leishmania braziliensis can either respond well or poorly to the treatment or heal spontaneously; It seems to be dependent on the parasite and/or host factors, but the mechanisms are not fully understood. We evaluated the in situ immune response in eighty-two active lesions from fifty-eight patients prior to treatment classified as early spontaneous regression (SRL-n = 14); treatment responders (GRL-n = 20); and non-responders (before first treatment/relapse, PRL1/PRL2-n = 24 each). Immunohistochemistry was used to identify cell/functional markers which were correlated with the clinical characteristics. PRL showed significant differences in lesion number/size, clinical evolution, and positive parasitological examinations when compared with the other groups. SRL presented a more efficient immune response than GRL and PRL, with higher IFN-γ/NOS2 and a lower percentage of macrophages, neutrophils, NK, B cells, and Ki-67+ cells. Compared to SRL, PRL had fewer CD4+ Tcells and more CD163+ macrophages. PRL1 had more CD68+ macrophages and Ki-67+ cells but less IFN-γ than GRL. PRL present a less efficient immune profile, which could explain the poor treatment response, while SRL had a more balanced immune response profile for lesion healing. Altogether, these evaluations suggest a differentiated profile of the organization of the inflammatory process for lesions of different tegumentary leishmaniasis evolution.
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Affiliation(s)
- Jéssica Leite-Silva
- Laboratory of Immunoparasitology, Oswaldo Cruz Institute (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21041-250, RJ, Brazil
| | - Carla Oliveira-Ribeiro
- Service of Oncological Dermatology-National Institute of Cancer (INCA), Rio de Janeiro 20570-120, RJ, Brazil
| | - Fernanda Nazaré Morgado
- Laboratory of Immunoparasitology, Oswaldo Cruz Institute (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21041-250, RJ, Brazil
| | - Maria Inês Fernandes Pimentel
- Laboratory of Clinical Research and Surveillance in Leishmaniasis (LAPCLIN VIGILEISH) National Institute of Infectology Evandro Chagas (INI), Fiocruz Rio de Janeiro 21041-250, RJ, Brazil
| | - Marcelo Rosandiski Lyra
- Laboratory of Clinical Research and Surveillance in Leishmaniasis (LAPCLIN VIGILEISH) National Institute of Infectology Evandro Chagas (INI), Fiocruz Rio de Janeiro 21041-250, RJ, Brazil
| | - Aline Fagundes
- Laboratory of Clinical Research and Surveillance in Leishmaniasis (LAPCLIN VIGILEISH) National Institute of Infectology Evandro Chagas (INI), Fiocruz Rio de Janeiro 21041-250, RJ, Brazil
| | - Luciana Freitas Campos Miranda
- Laboratory of Clinical Research and Surveillance in Leishmaniasis (LAPCLIN VIGILEISH) National Institute of Infectology Evandro Chagas (INI), Fiocruz Rio de Janeiro 21041-250, RJ, Brazil
| | - Claudia Maria Valete-Rosalino
- Laboratory of Clinical Research and Surveillance in Leishmaniasis (LAPCLIN VIGILEISH) National Institute of Infectology Evandro Chagas (INI), Fiocruz Rio de Janeiro 21041-250, RJ, Brazil
| | - Armando Oliveira Schubach
- Laboratory of Clinical Research and Surveillance in Leishmaniasis (LAPCLIN VIGILEISH) National Institute of Infectology Evandro Chagas (INI), Fiocruz Rio de Janeiro 21041-250, RJ, Brazil
| | - Fátima Conceição-Silva
- Laboratory of Immunoparasitology, Oswaldo Cruz Institute (IOC), Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21041-250, RJ, Brazil
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16
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Hu C, Priceputu E, Cool M, Chrobak P, Bouchard N, Forestier C, Lowell CA, Bénichou S, Hanna Z, Royal V, Jolicoeur P. NEF-Induced HIV-Associated Nephropathy Through HCK/LYN Tyrosine Kinases. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:702-724. [PMID: 36868467 PMCID: PMC10284032 DOI: 10.1016/j.ajpath.2023.02.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 03/05/2023]
Abstract
HIV-1-associated nephropathy (HIVAN) is a severe complication of HIV-1 infection. To gain insight into the pathogenesis of kidney disease in the setting of HIV, a transgenic (Tg) mouse model [CD4C/HIV-negative regulator factor (Nef)] was used in which HIV-1 nef expression is under control of regulatory sequences (CD4C) of the human CD4 gene, thus allowing expression in target cells of the virus. These Tg mice develop a collapsing focal segmental glomerulosclerosis associated with microcystic dilatation, similar to human HIVAN. To identify kidney cells permissive to the CD4C promoter, CD4C reporter Tg lines were used. They showed preferential expression in glomeruli, mainly in mesangial cells. Breeding CD4C/HIV Tg mice on 10 different mouse backgrounds showed that HIVAN was modulated by host genetic factors. Studies of gene-deficient Tg mice revealed that the presence of B and T cells and that of several genes was dispensable for the development of HIVAN: those involved in apoptosis (Trp53, Tnfsf10, Tnf, Tnfrsf1b, and Bax), in immune cell recruitment (Ccl3, Ccl2, Ccr2, Ccr5, and Cx3cr1), in nitric oxide (NO) formation (Nos3 and Nos2), or in cell signaling (Fyn, Lck, and Hck/Fgr). However, deletion of Src partially and that of Hck/Lyn largely abrogated its development. These data suggest that Nef expression in mesangial cells through hematopoietic cell kinase (Hck)/Lck/Yes novel tyrosine kinase (Lyn) represents important cellular and molecular events for the development of HIVAN in these Tg mice.
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Affiliation(s)
- Chunyan Hu
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Elena Priceputu
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Marc Cool
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Pavel Chrobak
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Nathalie Bouchard
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Clara Forestier
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
| | - Clifford A Lowell
- Department of Laboratory Medicine, University of California, San Francisco, California
| | - Serge Bénichou
- Insitut Cochin, Centre National de la Recherche Scientifique UMR8104, Université Paris Descartes and INSERM U1016, Paris, France
| | - Zaher Hanna
- Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada; Department of Medicine, University of Montreal, Montreal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Virginie Royal
- Department of Pathology and Cellular Biology, University of Montreal, Montreal, Quebec, Canada
| | - Paul Jolicoeur
- Department of Microbiology/Immunology, University of Montreal, Montreal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
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Recent Advances in the Development of Adenovirus-Vectored Vaccines for Parasitic Infections. Pharmaceuticals (Basel) 2023; 16:ph16030334. [PMID: 36986434 PMCID: PMC10058461 DOI: 10.3390/ph16030334] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/30/2023] [Accepted: 02/09/2023] [Indexed: 02/24/2023] Open
Abstract
Vaccines against parasites have lagged centuries behind those against viral and bacterial infections, despite the devastating morbidity and widespread effects of parasitic diseases across the globe. One of the greatest hurdles to parasite vaccine development has been the lack of vaccine strategies able to elicit the complex and multifaceted immune responses needed to abrogate parasitic persistence. Viral vectors, especially adenovirus (AdV) vectors, have emerged as a potential solution for complex disease targets, including HIV, tuberculosis, and parasitic diseases, to name a few. AdVs are highly immunogenic and are uniquely able to drive CD8+ T cell responses, which are known to be correlates of immunity in infections with most protozoan and some helminthic parasites. This review presents recent developments in AdV-vectored vaccines targeting five major human parasitic diseases: malaria, Chagas disease, schistosomiasis, leishmaniasis, and toxoplasmosis. Many AdV-vectored vaccines have been developed for these diseases, utilizing a wide variety of vectors, antigens, and modes of delivery. AdV-vectored vaccines are a promising approach for the historically challenging target of human parasitic diseases.
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18
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Spector BM, Shusterman DJ, Zhao K. Nasal nitric oxide flux from the paranasal sinuses. Curr Opin Allergy Clin Immunol 2023; 23:22-28. [PMID: 36373691 PMCID: PMC10170969 DOI: 10.1097/aci.0000000000000871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE OF REVIEW Upper airway nitric oxide (NO) is physiologically important in airway regulation and defense, and can be modulated by various airway inflammatory conditions, including allergic rhinitis and chronic rhinosinusitis - with and without polyposis. Paranasal sinuses serve as a NO 'reservoir', with concentrations typically exceeding those measured in lower airway (fractional exhaled NO or FeNO) by a few orders of magnitude. However, the dynamics of NO flux between the paranasal sinuses and main nasal airway, which are critical to respiratory NO emission, are poorly understood. RECENT FINDINGS Historically, NO emissions were thought to be contributed mostly by the maxillary sinuses (the largest sinuses) and active air movement (convection). However, recent anatomically-accurate computational modeling studies based on patients' CT scans showed that the ethmoid sinuses and diffusive transport dominate the process. SUMMARY These new findings may have a substantial impact on our view of nasal NO emission mechanisms and sinus physiopathology in general.
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Affiliation(s)
- Barak M. Spector
- Department of Otolaryngology – Head and Neck Surgery, The Ohio State University, Columbus, Ohio
| | - Dennis J. Shusterman
- Upper Airway Biology Laboratory, Department of Medicine, University of California, San Francisco, California, USA
| | - Kai Zhao
- Department of Otolaryngology – Head and Neck Surgery, The Ohio State University, Columbus, Ohio
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19
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Biomolecules Triggering Altered Food Intake during Pathogenic Challenge in Chicks. J Poult Sci 2023; 60:2023009. [PMID: 36969710 PMCID: PMC10031682 DOI: 10.2141/jpsa.2023009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 01/06/2023] [Indexed: 03/04/2023] Open
Abstract
Food intake is regulated by several complicated synergistic mechanisms that are affected by a variety of internal and external influences. Some of these factors include those that are released from pathogens such as bacteria, fungi, and viruses, and most of these factors are associated with suppression of the chick's food intake. Although chicks are well-known to decrease their food intake when they experience a pathogenic challenge, the mechanisms that mediate this type of satiety are poorly understood. One of the goals of our research group has been to better understand these mechanisms in chicks. We recently provided evidence that pathogen-associated molecular patterns, which are recognized by pattern-recognition receptors such as Toll-like receptors, likely contribute to satiety in chicks that are experiencing a pathogenic challenge. Additionally, we identified several inflammatory cytokines, including interleukin-1β, tumor necrosis factor-like cytokine 1A, prostaglandins, and nitric oxide, that likely contribute to satiety during a pathogenic challenge. This review summarizes the current knowledge on pathogen-induced satiety in chicks mainly accumulated through our recent research. The research will give good information to improve the loss of production during infection in poultry production in the future.
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20
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Conde L, Maciel G, de Assis GM, Freire-de-Lima L, Nico D, Vale A, Freire-de-Lima CG, Morrot A. Humoral response in Leishmaniasis. Front Cell Infect Microbiol 2022; 12:1063291. [PMID: 36579347 PMCID: PMC9791258 DOI: 10.3389/fcimb.2022.1063291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
Leishmaniasis presents different types of clinical manifestations that can be divided into cutaneous leishmaniasis and visceral leishmaniasis. The host's immune system, associated with genetic and nutritional factors, is strongly involved in the evolution of the disease or parasite escape. Humoral immunity is characterized by the production of antibodies capable of promoting neutralization, opsonization, and activation of the complement system. In this scenario, B lymphocytes produce antibodies that play an important role in Leishmania infection although neglected for a long time. Thus, relevant aspects in the establishment of Leishmania infection will be addressed, highlighting the importance of humoral immunity during the entire process of Leishmania infection.
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Affiliation(s)
- Luciana Conde
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gabriela Maciel
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gustavo Meira de Assis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Leonardo Freire-de-Lima
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Dirlei Nico
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - André Vale
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Alexandre Morrot
- Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil,Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil,*Correspondence: Alexandre Morrot,
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21
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Gao X, Sun B, Hou Y, Liu L, Sun J, Xu F, Li D, Hua H. Anti-breast cancer sinomenine derivatives via mechanisms of apoptosis induction and metastasis reduction. J Enzyme Inhib Med Chem 2022; 37:1870-1883. [PMID: 35801430 PMCID: PMC9272937 DOI: 10.1080/14756366.2022.2096020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Sinomenine, a morphinane-type isoquinoline-derived alkaloid, was first isolated from stems and roots of Sinomenium diversifolius (Miq.) in 1920. Later discovery by researchers confirmed various essential biological efficacy sinomenine exerted in vitro and in vivo. In this study, a series of 15 sinomenine/furoxan hybrid compounds were designed and synthesised in search of a TNBC drug candidate. Some of the target compounds exhibited strong antiproliferative activities against cancer cell lines, especially for TNBC cells, compared to positive controls. Among them, hybrid 7Cc exerted superior cytotoxic effects on cancer cell lines with exceptionally low IC50 (0.82 μM) against MDA-MB-231 cells with the highest safety index score. Further studies in mechanism displayed that 7Cc could induce an S phase cell cycle arrest, stimulate apoptosis in MDA-MB-231 cells, disrupt mitochondrial membrane potential and exert a genotoxic effect on DNA in cancer cells. In addition, 7Cc also notably inhibited MDA-MB-231 cells in both migration, invasion and adhesion.
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Affiliation(s)
- Xiang Gao
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Baojia Sun
- Yantai Valiant Pharmaceutical Co. Ltd, Shandong, China
| | - Yonglian Hou
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Lilin Liu
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Jianan Sun
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Fanxing Xu
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, China
| | - Dahong Li
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
| | - Huiming Hua
- Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China
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22
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Jayaraman A, Srinivasan S, Kar A, Harish B, Charan Raja MR, Uppuluri KB, Kar Mahapatra S. Oceanimonas sp. BPMS22-derived protein protease inhibitor induces anti-leishmanial immune responses through macrophage M2 to M1 repolarization. Int Immunopharmacol 2022; 112:109281. [DOI: 10.1016/j.intimp.2022.109281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 11/24/2022]
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Garay JA, Silva JE, Di Genaro MS, Davicino RC. The Multiple Faces of Nitric Oxide in Chronic Granulomatous Disease: A Comprehensive Update. Biomedicines 2022; 10:biomedicines10102570. [PMID: 36289832 PMCID: PMC9599698 DOI: 10.3390/biomedicines10102570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Nitric oxide (NO), a signaling molecule, regulates multiple biological functions, including a variety of physiological and pathological processes. In this regard, NO participates in cutaneous inflammations, modulation of mitochondrial functions, vascular diseases, COVID-19, neurologic diseases, and obesity. It also mediates changes in the skeletal muscle function. Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by the malfunction of phagocytes caused by mutations in some of the genes encoding subunits of the superoxide-generating phagocyte NADPH (NOX). The literature consulted shows that there is a relationship between the production of NO and the NADPH oxidase system, which regulates the persistence of NO in the medium. Nevertheless, the underlying mechanisms of the effects of NO on CGD remain unknown. In this paper, we briefly review the regulatory role of NO in CGD and its potential underlying mechanisms.
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Affiliation(s)
- Juan Agustín Garay
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina
| | - Juan Eduardo Silva
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis 5700, Argentina
| | - María Silvia Di Genaro
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis 5700, Argentina
| | - Roberto Carlos Davicino
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis 5700, Argentina
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis 5700, Argentina
- Correspondence:
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Gurjar D, Kumar Patra S, Bodhale N, Lenka N, Saha B. Leishmania intercepts IFN-γR signaling at multiple levels in macrophages. Cytokine 2022; 157:155956. [PMID: 35785668 DOI: 10.1016/j.cyto.2022.155956] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/13/2022] [Accepted: 06/24/2022] [Indexed: 11/26/2022]
Abstract
IFN-γ, a type 2 interferon and a cytokine, is critical for both innate and adaptive immunity. IFN-γ binds to the IFN-γRs on the cell membrane of macrophages, signals through JAK1-STAT-1 pathway and induces IFN-γ-stimulated genes (ISGs). As Leishmania amastigotes reside and replicate within macrophages, IFN-γ mediated macrophage activation eventuate in Leishmania elimination. As befits the principle of parasitism, the impaired IFN-γ responsiveness in macrophages ensures Leishmania survival. IFN-γ responsiveness is a function of integrated molecular events at multiple levels in the cells that express IFN-γ receptors. In Leishmania-infected macrophages, reduced IFN-γRα expression, impaired IFN-γRα and IFN-γRβ hetero-dimerization due to altered membrane lipid composition, reduced JAK-1 and STAT-1 phosphorylation but increased STAT-1 degradation and impaired ISGs induction collectively determine the IFN-γ responsiveness and the efficacy of IFN-γ induced antileishmanial function of macrophages. Therefore, parasite load is not only decided by the levels of IFN-γ produced but also by the IFN-γ responsiveness. Indeed, in Leishmania-infected patients, IFN-γ is produced but IFN-γ signalling is downregulated. However, the molecular mechanisms of IFN-γ responsiveness remain unclear. Therefore, we review the current understanding of IFN-γ responsiveness of Leishmania-infected macrophages.
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Affiliation(s)
- Dhiraj Gurjar
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India
| | | | - Neelam Bodhale
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India
| | - Nibedita Lenka
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
| | - Bhaskar Saha
- National Centre for Cell Science, Ganeshkhind, Pune 411007, India.
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Kopelyanskiy D, Desponds C, Prevel F, Rossi M, Migliorini R, Snäkä T, Eren RO, Claudinot S, Lye LF, Pasparakis M, Beverley SM, Fasel N. Leishmania guyanensis suppressed inducible nitric oxide synthase provoked by its viral endosymbiont. Front Cell Infect Microbiol 2022; 12:944819. [PMID: 36034693 PMCID: PMC9416488 DOI: 10.3389/fcimb.2022.944819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/27/2022] [Indexed: 11/13/2022] Open
Abstract
Inducible nitric oxide synthase (iNOS) is essential to the production of nitric oxide (NO), an efficient effector molecule against intracellular human pathogens such as Leishmania protozoan parasites. Some strains of Leishmania are known to bear a viral endosymbiont termed Leishmania RNA virus 1 (LRV1). Recognition of LRV1 by the innate immune sensor Toll-like receptor-3 (TLR3) leads to conditions worsening the disease severity in mice. This process is governed by type I interferon (type I IFNs) arising downstream of TLR3 stimulation and favoring the formation of secondary metastatic lesions. The formation of these lesions is mediated by the inflammatory cytokine IL-17A and occurs in the absence, or low level of, protective cytokine IFN-γ. Here, we described that the presence of LRV1 led to the initial expression of iNOS and low production of NO that failed to control infection. We subsequently showed that LRV1-triggered type I IFN was essential but insufficient to induce robust iNOS induction, which requires strong activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Leishmania guyanensis carrying LRV1 (LgyLRV1+) parasites mitigated strong iNOS production by limiting NF-kB activation via the induction of tumor necrosis factor-alpha-induced protein 3 (TNFAIP3), also known as A20. Moreover, our data suggested that production of LRV1-induced iNOS could be correlated with parasite dissemination and metastasis via elevated secretion of IL-17A in the draining lymph nodes. Our findings support an additional strategy by which LRV1-bearing Leishmania guyanensis evaded killing by nitric oxide and suggest that low levels of LRV1-induced NO might contribute to parasite metastasis.
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Affiliation(s)
| | - Chantal Desponds
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Florence Prevel
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Matteo Rossi
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Romain Migliorini
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Tiia Snäkä
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Remzi Onur Eren
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | | | - Lon-Fye Lye
- Department of Molecular Microbiology, School of Medicine, Washington University, St. Louis, MO, United States
| | - Manolis Pasparakis
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine, University of Cologne, Cologne, Germany
| | - Stephen M. Beverley
- Department of Molecular Microbiology, School of Medicine, Washington University, St. Louis, MO, United States
| | - Nicolas Fasel
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
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26
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de Queiroz AC, Barbosa G, de Oliveira VRT, de Mattos Alves H, Alves MA, Carregaro V, Santana da Silva J, Barreiro EJ, Alexandre-Moreira MS, Lima LM. Pre-clinical evaluation of LASSBio-1491: From in vitro pharmacokinetic study to in vivo leishmanicidal activity. PLoS One 2022; 17:e0269447. [PMID: 35666748 PMCID: PMC9170106 DOI: 10.1371/journal.pone.0269447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/21/2022] [Indexed: 11/19/2022] Open
Abstract
Leishmaniasis is a public health issue. It is among the top five parasitic illnesses worldwide and is one of the most neglected diseases. The current treatment disease includes limitations of toxicity, variable efficacy, high costs and inconvenient doses and treatment schedules. LASSBio-1736 was described as antileishmanial drug-candidate to cutaneous leishmaniasis, displaying plasma stability and with no preliminary signals of hepatic or renal toxicity. In this paper, we described the in vitro pharmacokinetic study of LASSBio-1491 (a less lipophilic isostere of LASSBio-1736) and it is in vitro and in vivo leishmanicidal activities. Our results demonstrated that LASSBio-1491 has high permeability, satisfactory aqueous solubility, long plasma and microsomal half-lives and low in vitro systemic clearance, suggesting a pharmacokinetic profile suitable for its use in a single daily dose. The antileishmanial effect of LASSBio-1491 was confirmed in vitro and in vivo. It exhibited no cytotoxic effect to mammalian cells and displayed good in –vivo effect against BALB/c mice infected with Leishmania major LV39 substrain, being 3 times more efficient than glucantime.
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Affiliation(s)
- Aline Cavalcanti de Queiroz
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratory of Pharmacology and Immunity (LaFI), Sector of Physiology and Pharmacology, ICBS, UFAL, Maceió, Alagoas, Brazil
- Laboratory of Microbiology, Immunology and Parasitology, Center for Medical Sciences, Campus Arapiraca, Federal University of Alagoas, Arapiraca, Alagoas, Brazil
| | - Gisele Barbosa
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Victória Regina Thomaz de Oliveira
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Hélio de Mattos Alves
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marina Amaral Alves
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vanessa Carregaro
- Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - João Santana da Silva
- Department of Biochemistry and Immunology, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Eliezer Jesus Barreiro
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
| | - Magna Suzana Alexandre-Moreira
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
- Laboratory of Pharmacology and Immunity (LaFI), Sector of Physiology and Pharmacology, ICBS, UFAL, Maceió, Alagoas, Brazil
- * E-mail: (LML); (MSAM)
| | - Lidia Moreira Lima
- National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR; http://www.inct-inofar.ccs.ufrj.br/), Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio, http://www.lassbio.icb.ufrj.br), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Rio de Janeiro, Brazil
- * E-mail: (LML); (MSAM)
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Shen J, Yu SF, Peng M, Lai DH, Hide G, Wu ZD, Lun ZR. iNOS is essential to maintain a protective Th1/Th2 response and the production of cytokines/chemokines against Schistosoma japonicum infection in rats. PLoS Negl Trop Dis 2022; 16:e0010403. [PMID: 35584107 PMCID: PMC9116669 DOI: 10.1371/journal.pntd.0010403] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 04/08/2022] [Indexed: 12/02/2022] Open
Abstract
Humans and a wide range of mammals are generally susceptible to Schistosoma infection, while some rodents such as Rattus rats and Microtus spp are not. We previously demonstrated that inherent high expression levels of nitric oxide (NO), produced by inducible nitric oxide synthase (iNOS), plays an important role in blocking the growth and development of Schistosoma japonicum in wild-type rats. However, the potential regulatory effects of NO on the immune system and immune response to S. japonicum infection in rats are still unknown. In this study, we used iNOS-knockout (KO) rats to determine the role of iNOS-derived NO in the immune system and immunopathological responses to S. japonicum infection in rats. Our data showed that iNOS deficiency led to weakened immune activity against S. japonicum infection. This was characterized by the impaired T cell responses and a significant decrease in S. japonicum-elicited Th2/Th1 responses and cytokine and chemokine-producing capability in the infected iNOS-KO rats. Unlike iNOS-KO mice, Th1-associated cytokines were also decreased in the absence of iNOS in rats. In addition, a profile of pro-inflammatory and pro-fibrogenic cytokines was detected in serum associated with iNOS deficiency. The alterations in immune responses and cytokine patterns were correlated with a slower clearance of parasites, exacerbated granuloma formation, and fibrosis following S. japonicum infection in iNOS-KO rats. Furthermore, we have provided direct evidence that high levels of NO in rats can promote the development of pulmonary fibrosis induced by egg antigens of S. japonicum, but not inflammation, which was negatively correlated with the expression of TGF-β3. These studies are the first description of the immunological and pathological profiles in iNOS-KO rats infected with S. japonicum and demonstrate key differences between the responses found in mice. Our results significantly enhance our understanding of the immunoregulatory effects of NO on defensive and immunopathological responses in rats and the broader nature of resistance to pathogens such as S. japonicum. Schistosomiasis is a zoonosis that affects more than 200 million people worldwide. A wide range of mammals, including mice, are permissive hosts of Schistosoma and develop chronic disease characterized by egg-granuloma formation and fibrosis after infection. Rats, on the other hand, are non-permissive hosts and develop efficient immune responses to eliminate the worms. Interestingly, schistosome eggs elicit a dominant Th2 immune response within mouse hosts, whereas rats with schistosomiasis develop a significant Th2 response in the absence of available egg production. The Th2 response in rats seems to play an essential role in the protection of the host against Schistosoma. So far, the factors that lead to the different immune responses to Schistosoma infection in both hosts have not been demonstrated. In this study, our results show that an iNOS-dependent mechanism maintains the function of the immune system in rats by modulating CD4+ T cell-mediated Th1/Th2-associated cytokine responses and chemokine production. Additionally, the absence of iNOS led to slow clearance of parasites, increases in the development of worms, and an exacerbation of granuloma formation and fibrosis in rats. Furthermore, high levels of NO in rats can promote the development of fibrosis induced by inflammation (rapid inflammatory repair). Therefore, this study demonstrates that the difference in iNOS levels between mice and rats is responsible for the different immune responses and outcomes induced by schistosome infection in both hosts.
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Affiliation(s)
- Jia Shen
- Department of Parasitology and Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, P.R. China
| | - Si-fei Yu
- Clinical Research Institute, The First People’s Hospital of Foshan, Foshan, P.R. China
| | - Mei Peng
- Department of Parasitology and Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, P.R. China
| | - De-Hua Lai
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Geoff Hide
- Ecosystems and Environment Research Centre and Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Salford, United Kingdom
| | - Zhong-Dao Wu
- Department of Parasitology and Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, P.R. China
- Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, Guangdong, P.R. China
- * E-mail: (Z-DW); (Z-RL)
| | - Zhao-Rong Lun
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
- * E-mail: (Z-DW); (Z-RL)
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Understanding the Cellular Sources of the Fractional Exhaled Nitric Oxide (FeNO) and Its Role as a Biomarker of Type 2 Inflammation in Asthma. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5753524. [PMID: 35547356 PMCID: PMC9085317 DOI: 10.1155/2022/5753524] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/20/2022] [Indexed: 11/18/2022]
Abstract
Fractional exhaled nitric oxide (FeNO) has gained great clinical importance as a biomarker of type 2 inflammation in chronic airway diseases such as asthma. FeNO originates primarily in the bronchial epithelium and is produced in large quantities by the enzyme inducible nitric oxide synthase (iNOS). It should be noted that nitric oxide (NO) produced at femtomolar to picomolar levels is fundamental for respiratory physiology. This basal production is induced in the bronchial epithelium by interferon gamma (IFNγ) via Janus kinases (JAK)/STAT-1 signaling. However, when there is an increase in the expression of type 2 inflammatory cytokines such as IL-4 and IL-13, the STAT-6 pathway is activated, leading to overexpression of iNOS and consequently to an overproduction of airway NO. Increased NO levels contributes to bronchial hyperreactivity and mucus hypersecretion, increases vascular permeability, reduces ciliary heartbeat, and promotes free radical production, airway inflammation, and tissue damage. In asthmatic patients, FeNO levels usually rise above 25 parts per billion (ppb) and its follow-up helps to define asthma phenotype and to monitor the effectiveness of corticosteroid treatment and adherence to treatment. FeNO is also very useful to identify those severe asthma patients that might benefit of personalized therapies with monoclonal antibodies. In this review, we revised the cellular and molecular mechanisms of NO production in the airway and its relevance as a biomarker of type 2 inflammation in asthma.
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Abstract
Leishmaniasis is a zoonotic and vector-borne infectious disease that is caused by the genus Leishmania belonging to the trypanosomatid family. The protozoan parasite has a digenetic life cycle involving a mammalian host and an insect vector. Leishmaniasisis is a worldwide public health problem falling under the neglected tropical disease category, with over 90 endemic countries, and approximately 1 million new cases and 20,000 deaths annually. Leishmania infection can progress toward the development of species–specific pathologic disorders, ranging in severity from self-healing cutaneous lesions to disseminating muco-cutaneous and fatal visceral manifestations. The severity and the outcome of leishmaniasis is determined by the parasite’s antigenic epitope characteristics, the vector physiology, and most importantly, the immune response and immune status of the host. This review examines the nature of host–pathogen interaction in leishmaniasis, innate and adaptive immune responses, and various strategies that have been employed for vaccine development.
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The nitric oxide pathway is involved in the anti-inflammatory effect of the rutheniumcomplex [Ru(bpy)2(2-MIM)(NO)](PF6)3. Eur J Pharmacol 2022; 921:174869. [PMID: 35247379 DOI: 10.1016/j.ejphar.2022.174869] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 02/28/2022] [Indexed: 12/15/2022]
Abstract
Metal coordination complexes are chemotherapeutic and anti-inflammatory agents. The ruthenium complex FOR811A ([Ru(bpy)2(2-MIM)Cl](PF6)3) FOR811A was evaluated in mice models of acute inflammation and behavioral tests. Animals received FOR811A (3, 10 or 30 mg/Kg; i.p.), indomethacin (20 mg/Kg; i.p.), L-NAME (20 mg/Kg; i.v.) aminoguanidine (50 mg/Kg; i.p.) or dexamethasone (0.5 mg/Kg; s.c.) 30 min before inflammatory stimulation. Paw edema was induced by carrageenan (400 μg/paw), TNF-α or L-arginine (15 nmol/paw) (5 ng/paw) and evaluated by hydroplestimometry 4 h later. Peritonitis was induced by carrageenan (500 μg; i.p.) and evaluated 4 h later for hypernociception and quantification of total/differential leukocytes, total protein reduced glutathione (GSH) and myeloperoxidase (MPO). FOR811A inhibited the paw edema induced by carrageenan at 3 (64%; p < 0.0001), 10 (73%; p < 0.0001) and 30 mg/kg (66%; p < 0.0001), and at 10 mg/kg that induced with L-arginine by 75% or TNF-α by 55% (p = 0.0012). Paw tissues histological analysis showed reduction in mast cells (46%; p = 0.0027), leukocyte infiltrate (66%; p < 0.0001), edema and hemorrhagic areas. Immunohistochemical evaluation revealed inhibition of iNOS (62%; p < 0.0001) and TNF-α (35%; p < 0.0001). In the peritonitis model FOR811A increased (2.8X; p < 0.0001) hypernociceptive threshold, reduced total leukocytes (29%; p < 0.0001), neutrophils (47%; p = 0.0003) and total proteins (36%; p = 0.0082). FOR811A also inhibited MPO (47%; p = 0.0296) and increased GSH (1.8X; p < 0.0001). In the behavioral tests, FOR811A reduced (30.6%) the number of crossings in the open field, and increased (16%) the number of falls in the Rota rod. Concluding, FOR811A presents anti-inflammatory and antioxidant effects, via nitric oxide pathway.
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Abstract
The parasitic trypanosomatids cause lethal and debilitating diseases, the leishmaniases, Chagas disease, and the African trypanosomiases, with major impacts on human and animal health. Sustained research has borne fruit by assisting efforts to reduce the burden of disease and by improving our understanding of fundamental molecular and cell biology. But where has the research primarily been conducted, and which research areas have received the most attention? These questions are addressed below using publication and citation data from the past few decades.
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Affiliation(s)
- David Horn
- The Wellcome Trust Centre for Anti-Infectives Research, Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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32
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Chen YF, Yu SF, Wu CY, Wu N, Shen J, Shen J, Gao JM, Wen YZ, Hide G, Lai DH, Lun ZR. Innate Resistance to Leishmania amazonensis Infection in Rat Is Dependent on NOS2. Front Microbiol 2021; 12:733286. [PMID: 34777283 PMCID: PMC8586549 DOI: 10.3389/fmicb.2021.733286] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/27/2021] [Indexed: 11/16/2022] Open
Abstract
Leishmania infection causes diverse clinical manifestations in humans. The disease outcome is complicated by the combination of many host and parasite factors. Inbred mouse strains vary in resistance to Leishmania major but are highly susceptible to Leishmania amazonensis infection. However, rats are highly resistant to L. amazonensis infection due to unknown mechanisms. We use the inducible nitric oxide synthase (Nos2) gene knockout rat model (Nos2−/− rat) to investigate the role of NOS2 against leishmania infection in rats. Our results demonstrated that diversion toward the NOS2 pathway is the key factor explaining the resistance of rats against L. amazonensis infection. Rats deficient in NOS2 are susceptible to L. amazonensis infection even though their immune response to infection is still strong. Moreover, adoptive transfer of NOS2 competent macrophages into Nos2−/− rats significantly reduced disease development and parasite load. Thus, we conclude that the distinct L-arginine metabolism, observed in rat macrophages, is the basis of the strong innate resistance to Leishmania. These data highlight that macrophages from different hosts possess distinctive properties and produce different outcomes in innate immunity to Leishmania infections.
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Affiliation(s)
- Yun-Fu Chen
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Si-Fei Yu
- Institute of Immunology and Key Laboratory of Tropical Disease Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Chang-You Wu
- Institute of Immunology and Key Laboratory of Tropical Disease Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Na Wu
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Jia Shen
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Juan Shen
- Institute of Immunology and Key Laboratory of Tropical Disease Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Jiang-Mei Gao
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yan-Zi Wen
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Geoff Hide
- Ecosystems and Environment Research Centre and Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Salford, United Kingdom
| | - De-Hua Lai
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Zhao-Rong Lun
- Guangdong Provincial Key Laboratory of Aquatic Economic Animals, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China.,Ecosystems and Environment Research Centre and Biomedical Research Centre, School of Science, Engineering and Environment, University of Salford, Salford, United Kingdom
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Wijnands KAP, Meesters DM, Vandendriessche B, Briedé JJ, van Eijk HMH, Brouckaert P, Cauwels A, Lamers WH, Poeze M. Microcirculatory Function during Endotoxemia-A Functional Citrulline-Arginine-NO Pathway and NOS3 Complex Is Essential to Maintain the Microcirculation. Int J Mol Sci 2021; 22:ijms222111940. [PMID: 34769369 PMCID: PMC8584871 DOI: 10.3390/ijms222111940] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 02/02/2023] Open
Abstract
Competition for the amino acid arginine by endothelial nitric-oxide synthase (NOS3) and (pro-)inflammatory NO-synthase (NOS2) during endotoxemia appears essential in the derangement of the microcirculatory flow. This study investigated the role of NOS2 and NOS3 combined with/without citrulline supplementation on the NO-production and microcirculation during endotoxemia. Wildtype (C57BL6/N background; control; n = 36), Nos2-deficient, (n = 40), Nos3-deficient (n = 39) and Nos2/Nos3-deficient mice (n = 42) received a continuous intravenous LPS infusion alone (200 μg total, 18 h) or combined with L-citrulline (37.5 mg, last 6 h). The intestinal microcirculatory flow was measured by side-stream dark field (SDF)-imaging. The jejunal intracellular NO production was quantified by in vivo NO-spin trapping combined with electron spin-resonance (ESR) spectrometry. Amino-acid concentrations were measured by high-performance liquid chromatography (HPLC). LPS infusion decreased plasma arginine concentration in control and Nos3−/− compared to Nos2−/− mice. Jejunal NO production and the microcirculation were significantly decreased in control and Nos2−/− mice after LPS infusion. No beneficial effects of L-citrulline supplementation on microcirculatory flow were found in Nos3−/− or Nos2−/−/Nos3−/− mice. This study confirms that L-citrulline supplementation enhances de novo arginine synthesis and NO production in mice during endotoxemia with a functional NOS3-enzyme (control and Nos2−/− mice), as this beneficial effect was absent in Nos3−/− or Nos2−/−/Nos3−/− mice.
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Affiliation(s)
- Karolina A. P. Wijnands
- Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands; (D.M.M.); (H.M.H.v.E.); (M.P.)
- Correspondence: ; Tel.: +31-650-513-913
| | - Dennis M. Meesters
- Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands; (D.M.M.); (H.M.H.v.E.); (M.P.)
- Department of Genetics & Cell Biology, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands
| | - Benjamin Vandendriessche
- VIB Inflammation Research Center, 9052 Ghent, Belgium; (B.V.); (P.B.); (A.C.)
- Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
- Byteflies, 2600 Antwerp, Belgium
- Department of Electrical, Computer and Systems Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jacob J. Briedé
- Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands;
| | - Hans M. H. van Eijk
- Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands; (D.M.M.); (H.M.H.v.E.); (M.P.)
| | - Peter Brouckaert
- VIB Inflammation Research Center, 9052 Ghent, Belgium; (B.V.); (P.B.); (A.C.)
- Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
| | - Anje Cauwels
- VIB Inflammation Research Center, 9052 Ghent, Belgium; (B.V.); (P.B.); (A.C.)
- Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium
- Orionis Biosciences, 9052 Ghent, Belgium
| | - Wouter H. Lamers
- Department of Anatomy & Embryology, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands;
| | - Martijn Poeze
- Department of Surgery, NUTRIM School of Nutrition, Translational Research in Metabolism, Maastricht University Medical Center, 6229 ER Maastricht, The Netherlands; (D.M.M.); (H.M.H.v.E.); (M.P.)
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Volpedo G, Pacheco-Fernandez T, Bhattacharya P, Oljuskin T, Dey R, Gannavaram S, Satoskar AR, Nakhasi HL. Determinants of Innate Immunity in Visceral Leishmaniasis and Their Implication in Vaccine Development. Front Immunol 2021; 12:748325. [PMID: 34712235 PMCID: PMC8546207 DOI: 10.3389/fimmu.2021.748325] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/24/2021] [Indexed: 12/22/2022] Open
Abstract
Leishmaniasis is endemic to the tropical and subtropical regions of the world and is transmitted by the bite of an infected sand fly. The multifaceted interactions between Leishmania, the host innate immune cells, and the adaptive immunity determine the severity of pathogenesis and disease development. Leishmania parasites establish a chronic infection by subversion and attenuation of the microbicidal functions of phagocytic innate immune cells such as neutrophils, macrophages and dendritic cells (DCs). Other innate cells such as inflammatory monocytes, mast cells and NK cells, also contribute to resistance and/or susceptibility to Leishmania infection. In addition to the cytokine/chemokine signals from the innate immune cells, recent studies identified the subtle shifts in the metabolic pathways of the innate cells that activate distinct immune signal cascades. The nexus between metabolic pathways, epigenetic reprogramming and the immune signaling cascades that drive the divergent innate immune responses, remains to be fully understood in Leishmania pathogenesis. Further, development of safe and efficacious vaccines against Leishmaniasis requires a broader understanding of the early interactions between the parasites and innate immune cells. In this review we focus on the current understanding of the specific role of innate immune cells, the metabolomic and epigenetic reprogramming and immune regulation that occurs during visceral leishmaniasis, and the strategies used by the parasite to evade and modulate host immunity. We highlight how such pathways could be exploited in the development of safe and efficacious Leishmania vaccines.
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Affiliation(s)
- Greta Volpedo
- Departments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Thalia Pacheco-Fernandez
- Departments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Parna Bhattacharya
- Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Timur Oljuskin
- Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Ranadhir Dey
- Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Sreenivas Gannavaram
- Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
| | - Abhay R Satoskar
- Departments of Pathology and Microbiology, Wexner Medical Center, The Ohio State University, Columbus, OH, United States
| | - Hira L Nakhasi
- Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States
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Role of nitric oxide on zymosan-induced inhibition of crop emptying in chicks. Comp Biochem Physiol A Mol Integr Physiol 2021; 261:111057. [PMID: 34419574 DOI: 10.1016/j.cbpa.2021.111057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/10/2021] [Accepted: 08/14/2021] [Indexed: 01/03/2023]
Abstract
Zymosan, a component of yeast cell walls, reduces feed passage through the digestive tract in chicks (Gallus gallus), although the mechanism mediating this effect is poorly understood. Nitric oxide (NO) is associated with a variety of biological actions including effects on the immune system. In addition, it has been suggested that NO is involved in relaxation of the digestive tract and affects feed passage in mammals. It is therefore possible that NO might be related to zymosan-induced reduction of feed passage in chicks. However, the role of NO on the effect of zymosan feed passage has not been clarified yet. Thus, the purpose of the present study was to investigate whether NO is associated with zymosan-induced alteration of feed passage in chicks. Intraperitoneal (IP) injection of zymosan significantly increased plasma nitrate and nitrite (NOx) concentrations at 6 h after injection. Zymosan-induced elevation of plasma NOx concentration was abolished by co-injection of S-methylisothiourea (SMT), a selective inhibitor for inducible NO synthase (iNOS), indicating that zymosan facilitated the induction of iNOS. Furthermore, because zymosan increased iNOS mRNA expression in the digestive tract, NO is likely associated with the effect of zymosan on the digestive tract. IP injection of NO donors significantly decreased crop emptying rate, suggesting that NO functions as an inhibitor of crop emptying. This result implied that zymosan stimulates NO production by the induction of iNOS in the digestive tract and thereby inhibits crop emptying rate. However, the co-injection of SMT did not attenuate the inhibitory effect of zymosan on crop emptying. The present study provides evidence that some changes in the digestive tract caused by zymosan are mediated by iNOS-induced NO in chicks, but NO does not mediate the effect of zymosan on feed passage through the crop.
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HIV-1 Nef Induces Hck/Lyn-Dependent Expansion of Myeloid-Derived Suppressor Cells Associated with Elevated Interleukin-17/G-CSF Levels. J Virol 2021; 95:e0047121. [PMID: 34106001 PMCID: PMC8354241 DOI: 10.1128/jvi.00471-21] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection causes myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD14+ CD16+) through largely unknown cellular and molecular pathways. The mouse cells thought to be equivalent to human CD14+ CD16+ cells are CD11b+ Gr1+ myeloid-derived suppressor cells (MDSC). We used HIV transgenic (Tg) mouse models to study MDSC, namely, CD4C/Nef Tg mice expressing nef in dendritic cells (DC), pDC, CD4+ T, and other mature and immature myeloid cells and CD11c/Nef Tg mice with a more restricted expression, mainly in DC and pDC. Both Tg strains showed expansion of granulocytic and CD11b+ Gr1low/int cells with MDSC characteristics. Fetal liver cell transplantation revealed that this expansion was stroma-independent and abrogated in mixed Tg/non-Tg 50% chimera. Tg bone marrow (BM) erythroid progenitors were decreased and myeloid precursors increased, suggesting an aberrant differentiation likely driving CD11b+ Gr1+ cell expansion, apparently cell autonomously in CD4C/Nef Tg mice and likely through a bystander effect in CD11c/Nef Tg mice. Hck was activated in Tg spleen, and Nef-mediated CD11b+ Gr1+ cell expansion was abrogated in Hck/Lyn-deficient Nef Tg mice, indicating a requirement of Hck/Lyn for this Nef function. IL-17 and granulocyte colony-stimulating factor (G-CSF) were elevated in Nef Tg mice. Increased G-CSF levels were normalized in Tg mice treated with anti-IL-17 antibodies. Therefore, Nef expression in myeloid precursors causes severe BM failure, apparently cell autonomously. More cell-restricted expression of Nef in DC and pDC appears sufficient to induce BM differentiation impairment, granulopoiesis, and expansion of MDSC at the expense of erythroid maturation, with IL-17→G-CSF as one likely bystander contributor. IMPORTANCE HIV-1 and SIV infection often lead to myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD14+ CD16+), with the latter likely involved in neuroAIDS. We found that some transgenic (Tg) mouse models of AIDS also develop accumulation of mature and immature cells of the granulocytic lineage, decreased erythroid precursors, and expansion of MDSC (equivalent to human CD14+ CD16+ cells). We identified Nef as being responsible for these phenotypes, and its expression in mouse DC appears sufficient for their development through a bystander mechanism. Nef expression in myeloid progenitors may also favor myeloid cell expansion, likely in a cell-autonomous way. Hck/Lyn is required for the Nef-mediated accumulation of myeloid cells. Finally, we identified G-CSF under the control of IL-17 as one bystander mediator of MDSC expansion. Our findings provide a framework to determine whether the Nef>Hck/Lyn>IL-17>G-CSF pathway is involved in human AIDS and whether it represents a valid therapeutic target.
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Computational modeling of nasal nitric oxide flux from the paranasal sinuses: Validation against human experiment. Comput Biol Med 2021; 136:104723. [PMID: 34388459 DOI: 10.1016/j.compbiomed.2021.104723] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/27/2021] [Accepted: 07/28/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Nitric oxide (NO) is important in respiratory physiology and airway defense. Although the paranasal sinuses are the major source of nasal NO, transport dynamics between the sinuses and nasal cavities are poorly understood. METHODS Exhaled nasal NO tracings were measured in two non-asthmatic subjects (one with allergic rhinitis, one without) using NO analyzer connected via face mask. We subsequently performed computational fluid dynamics NO emission simulations based on individual CT scans and compared to the experimental data. RESULTS Simulated exhaled NO tracings match well with experimental data (r > 0.84, p < 0.01) for both subjects, with measured peaks reaching 319.6 ppb in one subject (allergic-rhinitis), and 196.9 ppb in the other. The CFD simulation accurately captured the peak differences, even though the initial sinus NO concentration for both cases was set to the same 9000 ppb based on literature value. Further, the CFD simulation suggests that ethmoid sinuses contributed the most (>67%, other sinuses combined <33%) to total nasal NO emission in both cases and that diffusion contributes more than convective transport. By turning off diffusion (setting NO diffusivity to ~0), the NO emission peaks for both cases were reduced by >70%. CONCLUSION Historically, nasal NO emissions were thought to be contributed mostly by the maxillary sinuses (the largest sinuses) and active air movement (convection). Here, we showed that the ethmoid sinuses and diffusive transport dominate the process. These findings may have a substantial impact on our view of nasal NO emission mechanisms and sinus physiopathology in general.
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Duchesne C, Frescaline N, Blaise O, Lataillade JJ, Banzet S, Dussurget O, Rousseau A. Cold Atmospheric Plasma Promotes Killing of Staphylococcus aureus by Macrophages. mSphere 2021; 6:e0021721. [PMID: 34133202 PMCID: PMC8265637 DOI: 10.1128/msphere.00217-21] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/20/2021] [Indexed: 01/16/2023] Open
Abstract
Macrophages are important immune cells that are involved in the elimination of microbial pathogens. Following host invasion, macrophages are recruited to the site of infection, where they launch antimicrobial defense mechanisms. Effective microbial clearance by macrophages depends on phagocytosis and phagolysosomal killing mediated by oxidative burst, acidification, and degradative enzymes. However, some pathogenic microorganisms, including some drug-resistant bacteria, have evolved sophisticated mechanisms to prevent phagocytosis or escape intracellular degradation. Cold atmospheric plasma (CAP) is an emerging technology with promising bactericidal effects. Here, we investigated the effect of CAP on Staphylococcus aureus phagocytosis by RAW 264.7 macrophage-like cells. We demonstrate that CAP treatment increases intracellular concentrations of reactive oxygen species (ROS) and nitric oxide and promotes the elimination of both antibiotic-sensitive and antibiotic-resistant S. aureus by RAW 264.7 cells. This effect was inhibited by antioxidants indicating that the bactericidal effect of CAP was mediated by oxidative killing of intracellular bacteria. Furthermore, we show that CAP promotes the association of S. aureus to lysosomal-associated membrane protein 1 (LAMP-1)-positive phagosomes, in which bacteria are exposed to low pH and cathepsin D hydrolase. Taken together, our results provide the first evidence that CAP activates defense mechanisms of macrophages, ultimately leading to bacterial elimination. IMPORTANCE Staphylococcus aureus is the most frequent cause of skin and soft tissue infections. Treatment failures are increasingly common due to antibiotic resistance and the emergence of resistant strains. Macrophages participate in the first line of immune defense and are critical for coordinated defense against pathogenic bacteria. However, S. aureus has evolved sophisticated mechanisms to escape macrophage killing. In the quest to identify novel antimicrobial therapeutic approaches, we investigated the activity of cold atmospheric plasma (CAP) on macrophages infected with S. aureus. Here, we show that CAP treatment promotes macrophage ability to eliminate internalized bacteria. Importantly, CAP could trigger killing of both antibiotic-sensitive and antibiotic-resistant strains of S. aureus. While CAP did not affect the internalization capacity of macrophages, it increased oxidative-dependent bactericidal activity and promoted the formation of degradative phagosomes. Our study shows that CAP has beneficial effects on macrophage defense mechanisms and may potentially be useful in adjuvant antimicrobial therapies.
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Affiliation(s)
- Constance Duchesne
- Institut de Recherche Biomédicale des Armées, INSERM UMRS-MD 1197, Centre de Transfusion Sanguine des Armées, Clamart, France
- Laboratoire de physique des plasmas, École Polytechnique, Sorbonne Université, CNRS, Palaiseau, France
| | - Nadira Frescaline
- Institut de Recherche Biomédicale des Armées, INSERM UMRS-MD 1197, Centre de Transfusion Sanguine des Armées, Clamart, France
- Laboratoire de physique des plasmas, École Polytechnique, Sorbonne Université, CNRS, Palaiseau, France
| | - Océane Blaise
- Institut de Recherche Biomédicale des Armées, INSERM UMRS-MD 1197, Centre de Transfusion Sanguine des Armées, Clamart, France
- Laboratoire de physique des plasmas, École Polytechnique, Sorbonne Université, CNRS, Palaiseau, France
| | - Jean-Jacques Lataillade
- Institut de Recherche Biomédicale des Armées, INSERM UMRS-MD 1197, Centre de Transfusion Sanguine des Armées, Clamart, France
| | - Sébastien Banzet
- Institut de Recherche Biomédicale des Armées, INSERM UMRS-MD 1197, Centre de Transfusion Sanguine des Armées, Clamart, France
| | - Olivier Dussurget
- Institut Pasteur, Unité de Recherche Yersinia, Département de Microbiologie, Paris, France
- Université de Paris, Sorbonne Paris Cité, Paris, France
| | - Antoine Rousseau
- Laboratoire de physique des plasmas, École Polytechnique, Sorbonne Université, CNRS, Palaiseau, France
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Volpedo G, Pacheco-Fernandez T, Holcomb EA, Cipriano N, Cox B, Satoskar AR. Mechanisms of Immunopathogenesis in Cutaneous Leishmaniasis And Post Kala-azar Dermal Leishmaniasis (PKDL). Front Cell Infect Microbiol 2021; 11:685296. [PMID: 34169006 PMCID: PMC8217655 DOI: 10.3389/fcimb.2021.685296] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/24/2021] [Indexed: 12/18/2022] Open
Abstract
Leishmaniasis is a neglected tropical disease that affects 12 million people worldwide. The disease has high morbidity and mortality rates and is prevalent in over 80 countries, leaving more than 300 million people at risk of infection. Of all of the manifestations of this disease, cutaneous leishmaniasis (CL) is the most common form and it presents as ulcerating skin lesions that can self-heal or become chronic, leading to disfiguring scars. This review focuses on the different pathologies and disease manifestations of CL, as well as their varying degrees of severity. In particular, this review will discuss self-healing localized cutaneous leishmaniasis (LCL), leishmaniasis recidivans (LR), mucocutaneous leishmaniasis (MCL), anergic diffuse cutaneous leishmaniasis (ADCL), disseminated leishmaniasis (DL), and Post Kala-azar Dermal Leishmaniasis (PKDL), which is a cutaneous manifestation observed in some visceral leishmaniasis (VL) patients after successful treatment. The different clinical manifestations of CL are determined by a variety of factors including the species of the parasites and the host's immune response. Specifically, the balance between the pro and anti-inflammatory mediators plays a vital role in the clinical presentation and outcome of the disease. Depending upon the immune response, Leishmania infection can also transition from one form of the disease to another. In this review, different forms of cutaneous Leishmania infections and their immunology are described.
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Affiliation(s)
- Greta Volpedo
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Microbiology, College of Arts and Sciences, The Ohio State University, Columbus, OH, United States
| | - Thalia Pacheco-Fernandez
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Erin A. Holcomb
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Natalie Cipriano
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Blake Cox
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Abhay R. Satoskar
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States
- Department of Microbiology, College of Arts and Sciences, The Ohio State University, Columbus, OH, United States
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Liu X, Zhang D, Wang H, Ren Q, Li B, Wang L, Zheng G. MiR-451a enhances the phagocytosis and affects both M1 and M2 polarization in macrophages. Cell Immunol 2021; 365:104377. [PMID: 34004369 DOI: 10.1016/j.cellimm.2021.104377] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/20/2021] [Accepted: 05/05/2021] [Indexed: 12/16/2022]
Abstract
Leukemia associated macrophages (LAMs), which are different from tumor-associated macrophages as well as classical M1 and M2 macrophages, are specifically activated by leukemic microenvironment. We have reported the heterogeneity of gene expression profiles in LAMs. However, the expression profiles of microRNA (miRNA) in LAMs and their regulatory mechanisms have not been established. Here, the expression profiles of miRNA in LAMs from bone marrow and spleen of acute myeloid leukemia mice were analyzed. Then, the effects of miR-451a, which was upregulated in LAMs, on macrophages were studied by transfecting miRNA mimic to peritoneal macrophages. The results showed that overexpression of miR-451a altered the morphology, enhanced the phagocytic ability of macrophages, and promotes the expression of differentiation marker CD11b in macrophages. Furthermore, miR-451a increased the proliferation capacity of both M1- and M2-polarized macrophages, but not M0 macrophages. Moreover, miR-451a further enhanced the expression of iNOS upon M1 activation. Therefore, our results reveal the miRNA expression profiles in LAMs, and broaden the knowledge about miRNA regulation in macrophages.
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Affiliation(s)
- Xiaoli Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China
| | - Dongyue Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China
| | - Hao Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China
| | - Qian Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China
| | - Bin Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China
| | - Lina Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
| | - Guoguang Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
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Rostami MN, Khamesipour A. Potential biomarkers of immune protection in human leishmaniasis. Med Microbiol Immunol 2021; 210:81-100. [PMID: 33934238 PMCID: PMC8088758 DOI: 10.1007/s00430-021-00703-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 03/22/2021] [Indexed: 12/30/2022]
Abstract
Leishmaniasis is a vector-borne neglected tropical disease endemic in over 100 countries around the world. Available control measures are not always successful, therapeutic options are limited, and there is no vaccine available against human leishmaniasis, although several candidate antigens have been evaluated over the last decades. Plenty of studies have aimed to evaluate the immune response development and a diverse range of host immune factors have been described to be associated with protection or disease progression in leishmaniasis; however, to date, no comprehensive biomarker(s) have been identified as surrogate marker of protection or exacerbation, and lack of enough information remains a barrier for vaccine development. Most of the current understanding of the role of different markers of immune response in leishmaniasis has been collected from experimental animal models. Although the data generated from the animal models are crucial, it might not always be extrapolated to humans. Here, we briefly review the events during Leishmania invasion of host cells and the immune responses induced against Leishmania in animal models and humans and their potential role as a biomarker of protection against human leishmaniasis.
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Affiliation(s)
| | - Ali Khamesipour
- Center for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, 14155-6383, Tehran, Iran.
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Li K, You T, Zhao P, Luo Y, Zhang D, Wei H, Wang Y, Yang J, Guan X, Kuang Z. Structural basis for the regulation of inducible nitric oxide synthase by the SPRY domain-containing SOCS box protein SPSB2, an E3 ubiquitin ligase. Nitric Oxide 2021; 113-114:1-6. [PMID: 33862200 DOI: 10.1016/j.niox.2021.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 02/12/2021] [Accepted: 04/09/2021] [Indexed: 11/28/2022]
Abstract
Relatively high concentration of nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) in response to a variety of stimuli is a source of reactive nitrogen species, an important weapon of host innate immune defense. The SPRY domain-containing SOCS box protein 2 (SPSB2) is an E3 ubiquitin ligase that regulates the lifetime of iNOS. SPSB2 interacts with the N-terminal region of iNOS via a binding site on the SPRY domain of SPSB2, and recruits an E3 ubiquitin ligase complex to polyubiquitinate iNOS, leading to its proteasomal degradation. Although critical residues for the SPSB2-iNOS interaction have been identified, structural basis for the interaction remains to be explicitly determined. In this study, we have determined a crystal structure of the N-terminal region of iNOS in complex with the SPRY domain of SPSB2 at 1.24 Å resolution. We have resolved the roles of some flanking residues, whose contribution to the SPSB2-iNOS interaction was structurally unclear previously. Furthermore, we have evaluated the effects of SPSB2 inhibitors on NO production using transient transfection and cell-penetrating peptide approaches, and found that such inhibitors can elevate NO production in RAW264.7 macrophages. These results thus provide a useful basis for the development of potent SPSB2 inhibitors as well as recruiting ligands for proteolysis targeting chimera (PROTAC) design.
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Affiliation(s)
- Kefa Li
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Tingting You
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Panqi Zhao
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Yanhong Luo
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Danting Zhang
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Huan Wei
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Yuhui Wang
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Jinjin Yang
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Xueyan Guan
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China
| | - Zhihe Kuang
- Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, 510632, China; Guangdong Provincial Biotechnology Drug and Engineering Technology Research Center, Guangzhou, 510632, China; National Engineering Research Center of Genetic Medicine, Guangzhou, 510632, China.
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Ramazani A, Karimi M, Hosseinzadeh Z, Rezayati S, Hanifehpour Y, Joo SW. Syntheses and Antitumor Properties of Furoxan Derivatives. CURR ORG CHEM 2021. [DOI: 10.2174/1385272825666210208183751] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cancer is the second leading cause of death in Iran, next to heart disease. Current
therapy suffers from the major limitations of side effects and drug resistance, so the characterization
of new structures that can be power-selective and less-toxic anticancer agents is the
main challenge to medicinal chemistry research. Furoxan (1,2,5-oxadiazole-2-oxide) is a crucial
compound with many medicinal and pharmaceutical properties. The most important aspect
of furoxan is the nitric oxide (NO) molecule. One of the most essential furoxan derivatives,
which could be utilized in medicinal goals and pharmaceutical affairs, is benzofuroxan.
Furoxan could be described as a NO-donating compound in a variety of reactions, which
could also appear as hybridised with different medicinal compounds. This review article presents
a summary of syntheses and antitumor properties of furoxan derivatives as possible
chemotherapy agents for cancer. Furoxan can inhibit tumor growth in vivo without any side
effects in normal cells. Furthermore, due to NO-releasing in high levels in vivo and a wide
range of anticancer compounds, furoxan derivatives and especially its hybridised compounds could be considered as
antitumor, cytotoxic and apoptosis compounds to be applied in the human body.
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Affiliation(s)
- Ali Ramazani
- Department of Chemistry, Faculty of Science, University of Zanjan, Zanjan 45371-38791, Iran
| | - Masoud Karimi
- Department of Chemistry, Faculty of Science, University of Zanjan, Zanjan 45371-38791, Iran
| | - Zahra Hosseinzadeh
- Department of Chemistry, Faculty of Science, University of Zanjan, Zanjan 45371-38791, Iran
| | - Sobhan Rezayati
- Department of Chemistry, Faculty of Science, University of Zanjan, Zanjan 45371-38791, Iran
| | - Younes Hanifehpour
- School of Mechanical Engineering, Yeungnam University, Gyeongsan 38541, Korea
| | - Sang Woo Joo
- School of Mechanical Engineering, Yeungnam University, Gyeongsan 38541, Korea
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Balderrama-Gutierrez G, Milovic A, Cook VJ, Islam MN, Zhang Y, Kiaris H, Belisle JT, Mortazavi A, Barbour AG. An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin. mBio 2021; 12:e00588-21. [PMID: 33849979 PMCID: PMC8092257 DOI: 10.1128/mbio.00588-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/04/2021] [Indexed: 12/13/2022] Open
Abstract
Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: Peromyscus leucopus, the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Mus musculus Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels. LPS-treated deermice showed signs of sickness similar to those of exposed mice and had similar increases in corticosterone levels and expression of interleukin 6 (IL-6), tumor necrosis factor, IL-1β, and C-reactive protein. By network analysis, the M. musculus response to LPS was characterized as cytokine associated, while the P. leucopus response was dominated by neutrophil activity terms. In addition, dichotomies in the expression levels of arginase 1 and nitric oxide synthase 2 and of IL-10 and IL-12 were consistent with type M1 macrophage responses in mice and type M2 responses in deermice. Analysis of metabolites in plasma and RNA in organs revealed species differences in tryptophan metabolism. Two genes in particular signified the different phenotypes of deermice and mice: the Slpi and Ibsp genes. Key RNA-seq findings for P. leucopus were replicated in older animals, in a systemic bacterial infection, and with cultivated fibroblasts. The findings indicate that P. leucopus possesses several adaptive traits to moderate inflammation in its balancing of infection resistance and tolerance.IMPORTANCE Animals that are natural carriers of pathogens that cause human diseases commonly manifest little or no sickness as a consequence of infection. Examples include the deermouse, Peromyscus leucopus, which is a reservoir for Lyme disease and several other disease agents in North America, and some types of bats, which are carriers of viruses with pathogenicity for humans. Mechanisms of this phenomenon of infection tolerance and entailed trade-off costs are poorly understood. Using a single injection of lipopolysaccharide (LPS) endotoxin as a proxy for infection, we found that deermice differed from the mouse (Mus musculus) in responses to LPS in several diverse pathways, including innate immunity, oxidative stress, and metabolism. Features distinguishing the deermice cumulatively would moderate downstream ill effects of LPS. Insights gained from the P. leucopus model in the laboratory have implications for studying infection tolerance in other important reservoir species, including bats and other types of wildlife.
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Affiliation(s)
- Gabriela Balderrama-Gutierrez
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Ana Milovic
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, California, USA
| | - Vanessa J Cook
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, California, USA
| | - M Nurul Islam
- Department of Microbiology, Immunology, & Pathology, College of Veterinary Medicine & Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Youwen Zhang
- Department of Drug Discovery & Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA
| | - Hippokratis Kiaris
- Peromyscus Genetic Stock Center, University of South Carolina, Columbia, South Carolina, USA
- Department of Medicine, School of Medicine, University of California Irvine, Irvine, California, USA
| | - John T Belisle
- Department of Microbiology, Immunology, & Pathology, College of Veterinary Medicine & Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Ali Mortazavi
- Department of Developmental and Cell Biology, School of Biological Sciences, University of California Irvine, Irvine, California, USA
| | - Alan G Barbour
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, California, USA
- Department of Medicine, School of Medicine, University of California Irvine, Irvine, California, USA
- Department of Ecology & Evolutionary Biology, School of Biological Sciences, University of California Irvine, Irvine, California, USA
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45
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The molecular basis of immune-based platelet disorders. Clin Sci (Lond) 2021; 134:2807-2822. [PMID: 33140828 DOI: 10.1042/cs20191101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/12/2020] [Accepted: 10/23/2020] [Indexed: 12/17/2022]
Abstract
Platelets have a predominant role in haemostasis, the maintenance of blood volume and emerging roles as innate immune cells, in wound healing and in inflammatory responses. Platelets express receptors that are important for platelet adhesion, aggregation, participation in inflammatory responses, and for triggering degranulation and enhancing thrombin generation. They carry a cargo of granules bearing enzymes, adhesion molecules, growth factors and cytokines, and have the ability to generate reactive oxygen species. The platelet is at the frontline of a host of cellular responses to invading pathogens, injury, and infection. Perhaps because of this intrinsic responsibility of a platelet to rapidly respond to thrombotic, pathological and immunological factors as part of their infantry role; platelets are susceptible to targeted attack by the adaptive immune system. Such attacks are often transitory but result in aberrant platelet activation as well as significant loss of platelet numbers and platelet function, paradoxically leading to elevated risks of both thrombosis and bleeding. Here, we discuss the main molecular events underlying immune-based platelet disorders with specific focus on events occurring at the platelet surface leading to activation and clearance.
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Tewari D, Sah AN, Bawari S, Nabavi SF, Dehpour AR, Shirooie S, Braidy N, Fiebich BL, Vacca RA, Nabavi SM. Role of Nitric Oxide in Neurodegeneration: Function, Regulation, and Inhibition. Curr Neuropharmacol 2020; 19:114-126. [PMID: 32348225 PMCID: PMC8033982 DOI: 10.2174/1570159x18666200429001549] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 03/17/2020] [Accepted: 04/24/2020] [Indexed: 12/14/2022] Open
Abstract
Reactive nitrogen species (RNS) and reactive oxygen species (ROS), collectively known as reactive oxygen and nitrogen species (RONS), are the products of normal cellular metabolism and interact with several vital biomolecules including nucleic acid, proteins, and membrane lipids and alter their function in an irreversible manner which can lead to cell death. There is an imperative role for oxidative stress in the pathogenesis of cognitive impairments and the development and progression of neural injury. Elevated production of higher amounts of nitric oxide (NO) takes place in numerous pathological conditions, such as neurodegenerative diseases, inflammation, and ischemia, which occur concurrently with elevated nitrosative/oxidative stress. The enzyme nitric oxide synthase (NOS) is responsible for the generation of NO in different cells by conversion of L-arginine (Arg) to L-citrulline. Therefore, the NO signaling pathway represents a viable therapeutic target. Naturally occurring polyphenols targeting the NO signaling pathway can be of major importance in the field of neurodegeneration and related complications. Here, we comprehensively review the importance of NO and its production in the human body and afterwards highlight the importance of various natural products along with their mechanisms against various neurodegenerative diseases involving their effect on NO production.
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Affiliation(s)
- Devesh Tewari
- Department of Pharmacognosy, School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India
| | - Archana N Sah
- Department of Pharmaceutical Sciences, Faculty of Technology, Bhimtal Campus, Kumaun University, Nainital, Uttarakhand 263136, India
| | - Sweta Bawari
- School of Pharmacy, Sharda University, Knowledge Park-III, Greater Noida, Uttar Pradesh, 201310, India
| | - Seyed F Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran
| | - Ahmad R Dehpour
- Department of Pharmacology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Shirooie
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Australia
| | - Bernd L Fiebich
- Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Rosa A Vacca
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Council of Research, Bari, Italy
| | - Seyed M Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran
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Miyajima M. Amino acids: key sources for immunometabolites and immunotransmitters. Int Immunol 2020; 32:435-446. [PMID: 32383454 DOI: 10.1093/intimm/dxaa019] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 05/07/2020] [Indexed: 12/20/2022] Open
Abstract
Immune-cell activation and functional plasticity are closely linked to metabolic reprogramming that is required to supply the energy and substrates for such dynamic transformations. During such processes, immune cells metabolize many kinds of molecules including nucleic acids, sugars and lipids, which is called immunometabolism. This review will mainly focus on amino acids and their derivatives among such metabolites and describe the functions of these molecules in the immune system. Although amino acids are essential for, and well known as, substrates for protein synthesis, they are also metabolized as energy sources and as substrates for functional catabolites. For example, glutamine is metabolized to produce energy through glutaminolysis and tryptophan is consumed to supply nicotinamide adenine dinucleotide, whereas arginine is metabolized to produce nitric acid and polyamine by nitric oxide synthase and arginase, respectively. In addition, serine is catabolized to produce nucleotides and to induce methylation reactions. Furthermore, in addition to their intracellular functions, amino acids and their derivatives are secreted and have extracellular functions as immunotransmitters. Many amino acids and their derivatives have been classified as neurotransmitters and their functions are clear as transmitters between nerve cells, or between nerve cells and immune cells, functioning as immunotransmitters. Thus, this review will describe the intracellular and external functions of amino acid from the perspective of immunometabolism and immunotransmission.
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Affiliation(s)
- Michio Miyajima
- Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Tsurumi-ku, Yokohama, Kanagawa, Japan
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48
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ACE2 in the renin-angiotensin system. Clin Sci (Lond) 2020; 134:3063-3078. [PMID: 33264412 DOI: 10.1042/cs20200478] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 01/01/2023]
Abstract
In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic.
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49
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Palmieri EM, McGinity C, Wink DA, McVicar DW. Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight. Metabolites 2020; 10:metabo10110429. [PMID: 33114647 PMCID: PMC7693038 DOI: 10.3390/metabo10110429] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/19/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune myeloid cells, like macrophages, increase production of cytokines and NO, which is important for pathogen killing. Under these proinflammatory circumstances, called “M1”, macrophages undergo a series of metabolic changes including rewiring of their tricarboxylic acid (TCA) cycle. Here, we review findings indicating that NO, through its interaction with heme and non-heme metal containing proteins, together with components of the electron transport chain, functions not only as a regulator of cell respiration, but also a modulator of intracellular cell metabolism. Moreover, diverse effects of NO and NO-derived reactive nitrogen species (RNS) involve precise interactions with different targets depending on concentration, temporal, and spatial restrictions. Although the role of NO in macrophage reprogramming has been in evidence for some time, current models have largely minimized its importance. It has, therefore, been hiding in plain sight. A review of the chemical properties of NO, past biochemical studies, and recent publications, necessitates that mechanisms of macrophage TCA reprogramming during stimulation must be re-imagined and re-interpreted as mechanistic results of NO exposure. The revised model of metabolic rewiring we describe here incorporates many early findings regarding NO biochemistry and brings NO out of hiding and to the forefront of macrophages immunometabolism.
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50
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Bogdan C. Macrophages as host, effector and immunoregulatory cells in leishmaniasis: Impact of tissue micro-environment and metabolism. Cytokine X 2020; 2:100041. [PMID: 33604563 PMCID: PMC7885870 DOI: 10.1016/j.cytox.2020.100041] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022] Open
Abstract
Leishmania are protozoan parasites that predominantly reside in myeloid cells within their mammalian hosts. Monocytes and macrophages play a central role in the pathogenesis of all forms of leishmaniasis, including cutaneous and visceral leishmaniasis. The present review will highlight the diverse roles of macrophages in leishmaniasis as initial replicative niche, antimicrobial effectors, immunoregulators and as safe hideaway for parasites persisting after clinical cure. These multiplex activities are either ascribed to defined subpopulations of macrophages (e.g., Ly6ChighCCR2+ inflammatory monocytes/monocyte-derived dendritic cells) or result from different activation statuses of tissue macrophages (e.g., macrophages carrying markers of of classical [M1] or alternative activation [M2]). The latter are shaped by immune- and stromal cell-derived cytokines (e.g., IFN-γ, IL-4, IL-10, TGF-β), micro milieu factors (e.g., hypoxia, tonicity, amino acid availability), host cell-derived enzymes, secretory products and metabolites (e.g., heme oxygenase-1, arginase 1, indoleamine 2,3-dioxygenase, NOS2/NO, NOX2/ROS, lipids) as well as by parasite products (e.g., leishmanolysin/gp63, lipophosphoglycan). Exciting avenues of current research address the transcriptional, epigenetic and translational reprogramming of macrophages in a Leishmania species- and tissue context-dependent manner.
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Key Words
- (L)CL, (localized) cutaneous leishmaniasis
- AHR, aryl hydrocarbon receptor
- AMP, antimicrobial peptide
- Arg, arginase
- Arginase
- CAMP, cathelicidin-type antimicrobial peptide
- CR, complement receptor
- DC, dendritic cells
- DCL, diffuse cutaneous leishmaniasis
- HO-1, heme oxygenase 1
- Hypoxia
- IDO, indoleamine-2,3-dioxygenase
- IFN, interferon
- IFNAR, type I IFN (IFN-α/β) receptor
- IL, interleukin
- Interferon-α/β
- Interferon-γ
- JAK, Janus kinase
- LPG, lipophosphoglycan
- LRV1, Leishmania RNA virus 1
- Leishmaniasis
- Macrophages
- Metabolism
- NCX1, Na+/Ca2+ exchanger 1
- NFAT5, nuclear factor of activated T cells 5
- NK cell, natural killer cell
- NO, nitric oxide
- NOS2 (iNOS), type 2 (or inducible) nitric oxide synthase
- NOX2, NADPH oxidase 2 (gp91 or cytochrome b558 β-subunit of Phox)
- Nitric oxide
- OXPHOS, mitochondrial oxidative phosphorylation
- PKDL, post kala-azar dermal leishmaniasis
- Phagocyte NADPH oxidase
- Phox, phagocyte NADPH oxidase
- RNS, reactive nitrogen species
- ROS, reactive oxygen species
- SOCS, suppressor of cytokine signaling
- STAT, signal transducer and activator of transcription
- TGF-β, transforming growth factor-beta
- TLR, toll-like receptor
- Th1 (Th2), type 1 (type2) T helper cell
- Tonicity
- VL, visceral leishmaniasis
- mTOR, mammalian/mechanistic target of rapamycin
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Affiliation(s)
- Christian Bogdan
- Mikrobiologisches Institut - klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, D-91054 Erlangen, Germany.,Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, D-91054 Erlangen, Germany
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