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Tang Y, Cao L, Jin J, Li T, Chen Y, Lu Y, Li T, Weiss LM, Pan G, Bao J, Zhou Z. Single-cell transcriptional responses of T cells during microsporidia infection. Commun Biol 2025; 8:567. [PMID: 40185986 PMCID: PMC11971339 DOI: 10.1038/s42003-025-07990-4] [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: 05/08/2024] [Accepted: 03/24/2025] [Indexed: 04/07/2025] Open
Abstract
T cells have been reported to play critical roles in preventing of microsporidia dissemination. However, there roles and functions of each subset remain unclear. Here in the study, we performed a thorough analysis of murine splenic T-cell response analysis via single-cell RNA sequencing during microsporidia E. cuniculi infection. We demonstrated that Type I T helper (Th1) cells, T follicular helper (Tfh) cells, effector CD8 + T cells and proliferating CD8 + T cells were activated and expanded after infection. Activated Th1 cells and Tfh cells presented significantly upregulated gene expression of Ifng and Il21, respectively. A subcluster of Th1 cells with high Csf1 expression was detected after infection. Subsets of activated CD8 + T cells were markedly enriched with high expression of cytotoxic-function related genes such as Gzma and Gzmb, whereas some active CD8 T cells were enriched with proliferation-function related genes Mki67 and Stmn1. Other subsets of T cells including NK T cells, Myb+ T cells, γδ T cells and Cxcr6+ T cells, were also analyzed in this study yet no expansion was observed. In summary, our findings provide in-depth and comprehensive insights into T-cell responses during microsporidia infection, which will be valuable for further investigations.
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Affiliation(s)
- Yunlin Tang
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Lu Cao
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Jiangyan Jin
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Tangxin Li
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Yebo Chen
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Yishan Lu
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Tian Li
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Louis M Weiss
- Department of Pathology, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
| | - Guoqing Pan
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Jialing Bao
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China.
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China.
| | - Zeyang Zhou
- State Key Laboratory of Resource Insects, Southwest University, Chongqing, China.
- Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China.
- College of Life Sciences, Chongqing Normal University, Chongqing, China.
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Bruno F, Georgiou C, Cunningham D, Bett L, Secchi MA, Atkinson S, González Antón S, Birch F, Langhorne J, Lo Celso C. Differential Response and Recovery Dynamics of HSPC Populations Following Plasmodium chabaudi Infection. Int J Mol Sci 2025; 26:2816. [PMID: 40141458 PMCID: PMC11943058 DOI: 10.3390/ijms26062816] [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: 11/28/2024] [Revised: 03/13/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs' acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.
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Affiliation(s)
- Federica Bruno
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Christiana Georgiou
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | | | - Lucy Bett
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
| | - Marine A. Secchi
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Samantha Atkinson
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Sara González Antón
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | - Flora Birch
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
| | | | - Cristina Lo Celso
- Department of Life Sciences, Imperial College London, London SW10 9NH, UK; (F.B.)
- Sir Francis Crick Institute, London NW1 1AT, UK
- Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London W12 0NN, UK
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3
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Gbedande K, Ibitokou SA, Endrino MJD, Yap GS, Brown MG, Stephens R. Heightened innate immune state induced by viral vector leads to enhanced response to challenge and prolongs malaria vaccine protection. iScience 2024; 27:111468. [PMID: 39758993 PMCID: PMC11697717 DOI: 10.1016/j.isci.2024.111468] [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: 06/13/2024] [Revised: 10/01/2024] [Accepted: 11/21/2024] [Indexed: 01/07/2025] Open
Abstract
Cytomegalovirus is a promising vaccine vector; however, mechanisms promoting CD4 T cell responses to challenge, by CMV as a vector, are unknown. The ability of MCMV to prolong immunity generated by short-lived malaria vaccine was tested. MCMV provided non-specific protection to challenge with Plasmodium and increased interleukin-12 (IL-12) and CD8α+ dendritic cell (DC) numbers through prolonged MCMV-dependent interferon gamma (IFN-γ) production. This late innate response to MCMV increased IL-12 upon challenge and increased the polyclonal CD4 effector T cell response to Plasmodium, protecting in an IL-12-dependent manner. Although Plasmodium-vaccine-induced protection decayed by d200, MCMV restored protection through IFN-γ. Mechanistically, protection depended on MCMV-induced-IFN-γ increasing CD8α+ DCs and IL-12p40. MCMV expressing a Plasmodium epitope increased parasite-specific CD4 effector and effector memory T cells persisting after malaria vaccination, both phenotypes reported to protect. Overall, enhanced innate cell status, a mechanism of heterologous protection by MCMV, led to a stronger T cell response to challenge.
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Affiliation(s)
- Komi Gbedande
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
- Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
| | - Samad A. Ibitokou
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
| | - Mark Joseph D. Endrino
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
| | - George S. Yap
- Center for Immunity and Inflammation, and Department of Medicine, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
| | - Michael G. Brown
- Department of Medicine, Division of Nephrology, and the Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA
| | - Robin Stephens
- Department of Internal Medicine, Division of Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555-0435, USA
- Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
- Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Cancer Center, 205 S. Orange Avenue, Newark, NJ 07103, USA
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
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Panda M, Das B, Bantun F, Panda AK, Wahid M, Mandal RK, Qusty NF, Haque S, Ravindran B. Differential differentiation of B cell lymphopoiesis in lethal and non-lethal murine malaria models. Biotechnol Genet Eng Rev 2024; 40:4120-4137. [PMID: 37144664 DOI: 10.1080/02648725.2023.2205200] [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: 01/02/2023] [Accepted: 04/16/2023] [Indexed: 05/06/2023]
Abstract
B cells in protection against malaria and need of experiencing many episodes in humans to achieve a state of immunity is largely unknown. The cellular basis of such defects in terms of B cell generation, maturation and trafficking was studied by taking Plasmodium chabaudi, a non-lethal and Plasmodium berghei, a lethal murine model. A flow cytometry (FCF) based evaluation was used to study alterations in generation and maintenance of B cells in patients with Plasmodium falciparum malaria as well as in murine malaria models. A significant accumulation of mature B cells in bone marrow and immature B cells in circulation was a feature observed only in lethal malaria. At peak parasitaemia, both the models induce a significant decrease in T2 (transitional) B cells with expansion of T1B cells. Studies in patients with acute Pf malaria showed a significant expansion of memory B cells and TB cells with a concomitant decrease in naive2 B cells as compared with healthy controls. This study clearly demonstrates that acute malarial infection induces major disturbances in B cell development in lymphoid organs and trafficking in periphery.
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Affiliation(s)
- Madhumita Panda
- Infectious Disease Biology Group, DBT-Institute of Life Sciences, Bhubaneswar, Odisha, India
| | - Bidyut Das
- Department of Internal Medicine, SCB Medical College, Cuttack, Odisha, India
| | - Farkad Bantun
- Department of Microbiology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Aditya K Panda
- Department of Biotechnology, Berhampur University, Bhanja Bihar, Berhampur, India
| | - Mohd Wahid
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Raju K Mandal
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Naeem F Qusty
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Balachandran Ravindran
- Infectious Disease Biology Group, DBT-Institute of Life Sciences, Bhubaneswar, Odisha, India
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Zhu Y, Zhou L, Mo L, Hong C, Pan L, Lin J, Qi Y, Tan S, Qian M, Hu T, Zhao Y, Qiu H, Lin P, Ma X, Yang Q. Plasmodium yoelii Infection Enhances the Expansion of Myeloid-Derived Suppressor Cells via JAK/STAT3 Pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:170-186. [PMID: 38819229 DOI: 10.4049/jimmunol.2300541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 05/07/2024] [Indexed: 06/01/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii-infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.
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Affiliation(s)
- Yiqiang Zhu
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
| | - Lu Zhou
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lengshan Mo
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Cansheng Hong
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Lingxia Pan
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Jie Lin
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yanwei Qi
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Simin Tan
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Manhongtian Qian
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Tengfei Hu
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Yi Zhao
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Huaina Qiu
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Peibin Lin
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Xiancai Ma
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, China
| | - Quan Yang
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
- Department of Pathogenic Biology and Immunology, Sino-French Hoffmann Institute, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
- Second Affiliated Hospital, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou Medical University, Guangzhou, China
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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6
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Cunningham KT, Mills KHG. Modulation of haematopoiesis by protozoal and helminth parasites. Parasite Immunol 2023; 45:e12975. [PMID: 36797216 PMCID: PMC10909493 DOI: 10.1111/pim.12975] [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: 12/13/2022] [Revised: 02/07/2023] [Accepted: 02/13/2023] [Indexed: 02/18/2023]
Abstract
During inflammation, haematopoietic stem cells (HSCs) in the bone marrow (BM) and periphery rapidly expand and preferentially differentiate into myeloid cells that mediate innate immune responses. HSCs can be directed into quiescence or differentiation by sensing alterations to the haematopoietic niche, including cytokines, chemokines, and pathogen-derived products. Most studies attempting to identify the mechanisms of haematopoiesis have focused on bacterial and viral infections. From intracellular protozoan infections to large multicellular worms, parasites are a global health burden and represent major immunological challenges that remain poorly defined in the context of haematopoiesis. Immune responses to parasites vary drastically, and parasites have developed sophisticated immunomodulatory mechanisms that allow development of chronic infections. Recent advances in imaging, genomic sequencing, and mouse models have shed new light on how parasites induce unique forms of emergency haematopoiesis. In addition, parasites can modify the haematopoiesis in the BM and periphery to improve their survival in the host. Parasites can also induce long-lasting modifications to HSCs, altering future immune responses to infection, inflammation or transplantation, a term sometimes referred to as central trained immunity. In this review, we highlight the current understanding of parasite-induced haematopoiesis and how parasites target this process to promote chronic infections.
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Affiliation(s)
- Kyle T. Cunningham
- Wellcome Centre for Integrative ParasitologyInstitute of Infection and Immunity, University of GlasgowGlasgowUK
| | - Kingston H. G. Mills
- Immune Regulation Research GroupTrinity Biomedical Sciences Institute, Trinity College DublinDublinIreland
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Liu Y, Zhao Y, Wu J, Liu T, Tang M, Yao Y, Xue P, He M, Xu Y, Zhang P, Gu M, Qu W, Zhang Y. Lithium impacts the function of hematopoietic stem cells via disturbing the endoplasmic reticulum stress and Hsp90 signaling. Food Chem Toxicol 2023; 181:114081. [PMID: 37783420 DOI: 10.1016/j.fct.2023.114081] [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: 07/31/2023] [Revised: 09/18/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
Lithium (Li) has been widely used in clinical therapy and new Li-ion battery industry. To date, the impact of Li on the development of immune cells is largely unknown. The aim of this study was to investigate the impact of Li on hematopoiesis. C57BL/6 (B6) mice were treated with 50 ppm LiCl, 200 ppm LiCl, or the control via drinking water for 3 months, and thereafter the hematopoiesis was evaluated. Treatment with Li increased the number of mature lymphoid cells while suppressing the number of mature myeloid cells in mice. In addition, a direct action of Li on hematopoietic stem cells (HSC) suppressed endoplasmic reticulum (ER) stress to reduce the proliferation of HSC in the bone marrow (BM), thus leading to fewer HSC in mice. On the other hand, the suppression of ER stress by Li exposure increased the expression of Hsp90, which promoted the potential of lymphopoiesis but did not impact that for myelopoiesis in HSC in the BM of mice. Moreover, in vitro treatment with Li also likely disturbed the ER stress-Hsp90 signaling, suppressed the proliferation, and increased the potential for lymphopoiesis in human HSC. Our study reveals a previously unrecognized toxicity of Li on HSC and may advance our understanding for the immunotoxicology of Li.
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Affiliation(s)
- Yalin Liu
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Yifan Zhao
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Jiaojiao Wu
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Ting Liu
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - MengKe Tang
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Ye Yao
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Peng Xue
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Miao He
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Fudan University, Shanghai, 200032, China
| | - Yanyi Xu
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Peng Zhang
- Huzhou Center for Disease Control and Prevention, Zhejiang, 313000, China.
| | - Minghua Gu
- Shanghai Municipal Center for Disease Control & Prevention, Shanghai, 200336, China.
| | - Weidong Qu
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China
| | - Yubin Zhang
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai, 200032, China.
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Herbert Mainero A, Spence PJ, Reece SE, Kamiya T. The impact of innate immunity on malaria parasite infection dynamics in rodent models. Front Immunol 2023; 14:1171176. [PMID: 37646037 PMCID: PMC10461630 DOI: 10.3389/fimmu.2023.1171176] [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: 02/21/2023] [Accepted: 07/07/2023] [Indexed: 09/01/2023] Open
Abstract
Decades of research have probed the molecular and cellular mechanisms that control the immune response to malaria. Yet many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to seek consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate, and statistically analyze infection dynamics in immune-deficient or -augmented mice to identify and quantify general trends and reveal sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen's h) for the difference in parasite burden between treatment and control groups ranging from 0.1475 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 7-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effect sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these hypotheses is necessary to translate understanding from model systems to human malaria.
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Affiliation(s)
- Alejandra Herbert Mainero
- Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Philip J. Spence
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Sarah E. Reece
- Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Tsukushi Kamiya
- Institute of Ecology and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Centre for Interdisciplinary Research in Biology, Collège de France, Paris, France
- HRB, National University of Ireland Galway, Galway, Ireland
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Maceiras AR, Silvério D, Gonçalves R, Cardoso MS, Saraiva M. Infection with hypervirulent Mycobacterium tuberculosis triggers emergency myelopoiesis but not trained immunity. Front Immunol 2023; 14:1211404. [PMID: 37383236 PMCID: PMC10296772 DOI: 10.3389/fimmu.2023.1211404] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023] Open
Abstract
Introduction During infection, bone marrow (BM) hematopoiesis is reprogrammed toward myeloid cell production, a mechanism named emergency myelopoiesis. In addition to replenishing myeloid cells, emergency myelopoiesis has been linked to trained immunity, a process that allows enhanced innate immune responses to secondary challenges. Although hematopoietic alterations during tuberculosis (TB) have been described and Mycobacterium tuberculosis may colonize the BM, studies using the mouse model of infection and the laboratory reference strain M. tuberculosis H37Rv have demonstrated limited emergency myelopoiesis and trained immunity. Methods To further address this issue, we aerosol- infected C57BL/6 mice with high doses of the hypervirulent M. tuberculosis isolate HN878 and monitored alterations to the BM. This experimental model better resembles the human blood immune signature of TB. Results and discussion We found increased frequencies of lineage-Sca-1+cKit+ (LSK) cells and the granulocyte/macrophage progenitor (GMP) population. At the mature cell level, we observed an increase of monocytes and neutrophils in the blood and lung, likely reflecting the increased BM myeloid output. Monocytes or monocyte-derived macrophages recovered from the BM of M. tuberculosis HN878-infected mice did not show signs of trained immunity, suggesting an uncoupling of emergency myelopoiesis and trained immunity in the BM. Surprisingly, M. tuberculosis HN878-induced emergency myelopoiesis was not fully dependent on IFNγ, as mice lacking this cytokine and infected under the same conditions as wild-type mice still presented BM alterations. These data expand our understanding of the immune response to M. tuberculosis and raise awareness of pathogen strain-imposed differences to host responses.
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Affiliation(s)
- Ana Raquel Maceiras
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal
| | - Diogo Silvério
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Doctoral Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Rute Gonçalves
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Doctoral Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
| | - Marcos S. Cardoso
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
| | - Margarida Saraiva
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal
- Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal
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10
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Leonardo L, Kenangalem E, Poespoprodjo JR, Noviyanti R, Price RN, Anstey NM, Minigo G, Kho S. Increased circulating myeloid-derived suppressor cells in vivax malaria and severe falciparum malaria. Malar J 2022; 21:255. [PMID: 36068577 PMCID: PMC9446641 DOI: 10.1186/s12936-022-04268-6] [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: 03/05/2022] [Accepted: 08/16/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Circulating myeloid-derived-suppressor-cells (MDSC) with immunosuppressive function are increased in human experimental Plasmodium falciparum infection, but have not been studied in clinical malaria. METHODS Using flow-cytometry, circulating polymorphonuclear-MDSC were evaluated in cryopreserved samples from patients with uncomplicated Plasmodium vivax (n = 8) and uncomplicated (n = 4) and severe (n = 16) falciparum malaria from Papua, Indonesia. RESULTS The absolute number of circulating polymorphonuclear-MDSC were significantly elevated in severe falciparum malaria patients compared to controls (n = 10). Polymorphonuclear-MDSC levels in uncomplicated vivax malaria were also elevated to levels comparable to that seen in severe falciparum malaria. CONCLUSION Control of expansion of immunosuppressive MDSC may be important for development of effective immune responses in falciparum and vivax malaria.
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Affiliation(s)
- Leo Leonardo
- Papuan Health and Community Development Foundation, Timika, Papua, Indonesia
| | - Enny Kenangalem
- Papuan Health and Community Development Foundation, Timika, Papua, Indonesia
| | - Jeanne R Poespoprodjo
- Papuan Health and Community Development Foundation, Timika, Papua, Indonesia
- Department of Pediatrics, University of Gadjah Mada, Yogyakarta, Indonesia
| | | | - Ric N Price
- Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX37LJ, UK
- Mahidol-Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Nicholas M Anstey
- Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
| | - Gabriela Minigo
- Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
- College of Health and Human Sciences, Charles Darwin University, Darwin, NT, Australia
| | - Steven Kho
- Papuan Health and Community Development Foundation, Timika, Papua, Indonesia.
- Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia.
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11
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Epigenetic Memories in Hematopoietic Stem and Progenitor Cells. Cells 2022; 11:cells11142187. [PMID: 35883630 PMCID: PMC9324604 DOI: 10.3390/cells11142187] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 11/16/2022] Open
Abstract
The recent development of next-generation sequencing (NGS) technologies has contributed to research into various biological processes. These novel NGS technologies have revealed the involvement of epigenetic memories in trained immunity, which are responses to transient stimulation and result in better responses to secondary challenges. Not only innate system cells, such as macrophages, monocytes, and natural killer cells, but also bone marrow hematopoietic stem cells (HSCs) have been found to gain memories upon transient stimulation, leading to the enhancement of responses to secondary challenges. Various stimuli, including microbial infection, can induce the epigenetic reprogramming of innate immune cells and HSCs, which can result in an augmented response to secondary stimulation. In this review, we introduce novel NGS technologies and their application to unraveling epigenetic memories that are key in trained immunity and summarize the recent findings in trained immunity. We also discuss our most recent finding regarding epigenetic memory in aged HSCs, which may be associated with the exposure of HSCs to aging-related stresses.
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12
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Barreira-Silva P, Melo-Miranda R, Nobrega C, Roque S, Serre-Miranda C, Borges M, Armada G, de Sá Calçada D, Behar SM, Appelberg R, Correia-Neves M. IFNγ and iNOS-Mediated Alterations in the Bone Marrow and Thymus and Its Impact on Mycobacterium avium-Induced Thymic Atrophy. Front Immunol 2021; 12:696415. [PMID: 34987496 PMCID: PMC8721011 DOI: 10.3389/fimmu.2021.696415] [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: 04/16/2021] [Accepted: 11/30/2021] [Indexed: 11/13/2022] Open
Abstract
Disseminated infection with the high virulence strain of Mycobacterium avium 25291 leads to progressive thymic atrophy. We previously showed that M. avium-induced thymic atrophy results from increased glucocorticoid levels that synergize with nitric oxide (NO) produced by interferon gamma (IFNγ) activated macrophages. Where and how these mediators act is not understood. We hypothesized that IFNγ and NO promote thymic atrophy through their effects on bone marrow (BM) T cell precursors and T cell differentiation in the thymus. We show that M. avium infection cause a reduction in the percentage and number of common lymphoid progenitors (CLP). Additionally, BM precursors from infected mice show an overall impaired ability to reconstitute thymi of RAGKO mice, in part due to IFNγ. Thymi from infected mice present an IFNγ and NO-driven inflammation. When transplanted under the kidney capsule of uninfected mice, thymi from infected mice are unable to sustain T cell differentiation. Finally, we observed increased thymocyte death via apoptosis after infection, independent of both IFNγ and iNOS; and a decrease on active caspase-3 positive thymocytes, which is not observed in the absence of iNOS expression. Together our data suggests that M. avium-induced thymic atrophy results from a combination of defects mediated by IFNγ and NO, including alterations in the BM T cell precursors, the thymic structure and the thymocyte differentiation.
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Affiliation(s)
- Palmira Barreira-Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
- *Correspondence: Palmira Barreira-Silva, ; Margarida Correia-Neves,
| | - Rita Melo-Miranda
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
| | - Claudia Nobrega
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
| | - Susana Roque
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
| | - Cláudia Serre-Miranda
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
| | - Margarida Borges
- Research Unit on Applied Molecular Biosciences (UCIBIO)/Rede de Química e Tecnologia (REQUINTE), Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Gisela Armada
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
| | - Daniela de Sá Calçada
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
| | - Samuel M. Behar
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, United States
| | - Rui Appelberg
- Instituto de Investigação e Inovação em Saúde (i3S), Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
- IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Margarida Correia-Neves
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- Life and Health Sciences Research Institute/Biomaterials, Biodegradables and Biomimetics Research Group (ICVS/3B’s), PT Government Associate Laboratory, Braga, Portugal
- Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- *Correspondence: Palmira Barreira-Silva, ; Margarida Correia-Neves,
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13
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Mun Y, Fazio S, Arrieta CN. Remodeling of the Bone Marrow Stromal Microenvironment During Pathogenic Infections. Curr Top Microbiol Immunol 2021; 434:55-81. [PMID: 34850282 DOI: 10.1007/978-3-030-86016-5_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The bone marrow (BM) is the primary hematopoietic organ and a hub in which organismal demands for blood cellular output are systematically monitored. BM tissues are additionally home to a plethora of mature immune cell types, providing functional environments for the activation of immune responses and acting as preferred anatomical reservoirs for cells involved in immunological memory. Stromal cells of the BM microenvironment crucially govern different aspects of organ function, by structuring tissue microanatomy and by directly providing essential regulatory cues to hematopoietic and immune components in distinct niches. Emerging evidence demonstrates that stromal networks are endowed with remarkable functional and structural plasticity. Stress-induced adaptations of stromal cells translate into demand-driven hematopoiesis. Furthermore, aberrations of stromal integrity arising from pathological conditions critically contribute to the dysregulation of BM function. Here, we summarize our current understanding of the alterations that pathogenic infections and ensuing inflammatory conditions elicit on the global topography of the BM microenvironment, the integrity of anatomical niches and cellular interactions, and ultimately, on the regulatory function of diverse stromal subsets.
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Affiliation(s)
- YeVin Mun
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Häldeliweg 4, 8032, Zurich, Switzerland
| | - Serena Fazio
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Häldeliweg 4, 8032, Zurich, Switzerland
| | - César Nombela Arrieta
- Department of Medical Oncology and Hematology, University and University Hospital Zurich, Häldeliweg 4, 8032, Zurich, Switzerland.
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14
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Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis. Cell Rep 2021; 37:109887. [PMID: 34706233 DOI: 10.1016/j.celrep.2021.109887] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/17/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022] Open
Abstract
In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the pro-inflammatory cytokine interferon gamma (IFN-γ). Interleukin-10 (IL-10) inhibits IFN-γ secretion, but paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work, we use different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also find that IL-10, unexpectedly, reprograms CD4 and CD8 T cells toward an activation state that includes IFN-γ production by these T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening additional perspectives for the design of IL-10-based immunotherapies.
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15
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Fresno M, Gironès N. Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection. Front Cell Infect Microbiol 2021; 11:737364. [PMID: 34513737 PMCID: PMC8430253 DOI: 10.3389/fcimb.2021.737364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous myeloid cells that expand in pathologic conditions as cancer, trauma, and infection. Although characterization of MDSCs is continuously revisited, the best feature is their suppressor activity. There are many markers for MDSC identification, it is distinctive that they express inducible nitric oxide synthase (iNOS) and arginase 1, which can mediate immune suppression. MDSCs can have a medullary origin as a result of emergency myelopoiesis, but also can have an extramedullary origin. Early studies on Trypanosoma cruzi infection showed severe immunosuppression, and several mechanisms involving parasite antigens and host cell mediators were described as inhibition of IL-2 and IL-2R. Another mechanism of immunosuppression involving tumor necrosis factor/interferon γ-dependent nitric oxide production by inducible nitric oxide synthase was also described. Moreover, other studies showed that nitric oxide was produced by CD11b+ Gr-1+ MDSCs in the spleen, and later iNOS and arginase 1 expressed in CD11b+Ly6C+Ly6Glo monocytic MDSC were found in spleen and heart of T. cruzi infected mice that suppressed T cell proliferation. Uncontrolled expansion of monocytic MDSCs leads to L-arginine depletion which hinders nitric oxide production leading to death. Supplement of L-arginine partially reverts L-arginine depletion and survival, suggesting that L-arginine could be administered along with anti-parasitical drugs. On the other hand, pharmacological inhibition of MDSCs leads to death in mice, suggesting that some expansion of MDSCs is needed for an efficient immune response. The role of signaling molecules mediating immune suppression as reactive oxygen species, reactive nitrogen species, as well as prostaglandin E2, characteristics of MDSCs, in T. cruzi infection is not fully understood. We review and discuss the role of these reactive species mediators produced by MDSCs. Finally, we discuss the latest results that link the SLAMF1 immune receptor with reactive oxygen species. Interaction of the parasite with the SLAMF1 modulates parasite virulence through myeloid cell infectivity and reactive oxygen species production. We discuss the possible strategies for targeting MDSCs and SLAMF1 receptor in acute Trypanosoma cruzi infection in mice, to evaluate a possible translational application in human acute infections.
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Affiliation(s)
- Manuel Fresno
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.,Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Group 12, Madrid, Spain
| | - Núria Gironès
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain.,Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Group 12, Madrid, Spain
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16
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Systemic bacterial infections affect dendritic cell development and function. Int J Med Microbiol 2021; 311:151517. [PMID: 34233227 DOI: 10.1016/j.ijmm.2021.151517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/29/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022] Open
Abstract
Dendritic cells (DCs) are critical in host defense against infection. DC depletion is an early event in the course of sepsis that may impair the host defense mechanisms. Here, we addressed whether DC depletion and dysfunction are pathogen-independent, mediated via pattern recognition receptors, and are due to impaired DC development upon systemic infection with the Gram-negative bacterium Escherichia coli and the Gram-positive pathogen Staphylococcus aureus. Infection with E. coli and S. aureus led to reduced numbers of splenic DC subsets and of DC progenitors in the bone marrow (BM) with this effect persisting significantly longer in mice infected with S. aureus than with E. coli. The reduction of DC subsets and their progenitors was mainly TLR-independent as was the infection-induced monopoiesis. Moreover, de novo DC development was impaired in mice infected with S. aureus, and BM cells from E. coli or S. aureus infected mice favored macrophage differentiation in vitro. As a consequence of reduced DC numbers and their reduced expression of MHC II less CD4+ and CD8+ T cells, especially Th1 and IFN-γ producing CD8+ T cells, could be detected in S. aureus compared to E. coli infected mice. These differences are reflected in the rapid killing of E. coli as opposed to an increase in bacterial load in S. aureus. In summary, our study supports the idea that systemic bacterial infections generally affect the number and development of DCs and thereby the T cell responses, but the magnitude is pathogen-dependent.
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17
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Modeling the Dynamics of T-Cell Development in the Thymus. ENTROPY 2021; 23:e23040437. [PMID: 33918050 PMCID: PMC8069328 DOI: 10.3390/e23040437] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/01/2021] [Accepted: 04/05/2021] [Indexed: 12/24/2022]
Abstract
The thymus hosts the development of a specific type of adaptive immune cells called T cells. T cells orchestrate the adaptive immune response through recognition of antigen by the highly variable T-cell receptor (TCR). T-cell development is a tightly coordinated process comprising lineage commitment, somatic recombination of Tcr gene loci and selection for functional, but non-self-reactive TCRs, all interspersed with massive proliferation and cell death. Thus, the thymus produces a pool of T cells throughout life capable of responding to virtually any exogenous attack while preserving the body through self-tolerance. The thymus has been of considerable interest to both immunologists and theoretical biologists due to its multi-scale quantitative properties, bridging molecular binding, population dynamics and polyclonal repertoire specificity. Here, we review experimental strategies aimed at revealing quantitative and dynamic properties of T-cell development and how they have been implemented in mathematical modeling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations. Furthermore, we summarize the current challenges to estimating in vivo cellular dynamics and to reaching a next-generation multi-scale picture of T-cell development.
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18
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Nahrendorf W, Ivens A, Spence PJ. Inducible mechanisms of disease tolerance provide an alternative strategy of acquired immunity to malaria. eLife 2021; 10:e63838. [PMID: 33752799 PMCID: PMC7987336 DOI: 10.7554/elife.63838] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 02/19/2021] [Indexed: 12/26/2022] Open
Abstract
Immunity to malaria is often considered slow to develop but this only applies to defense mechanisms that function to eliminate parasites (resistance). In contrast, immunity to severe disease can be acquired quickly and without the need for improved pathogen control (tolerance). Using Plasmodium chabaudi, we show that a single malaria episode is sufficient to induce host adaptations that can minimise inflammation, prevent tissue damage and avert endothelium activation, a hallmark of severe disease. Importantly, monocytes are functionally reprogrammed to prevent their differentiation into inflammatory macrophages and instead promote mechanisms of stress tolerance to protect their niche. This alternative fate is not underpinned by epigenetic reprogramming of bone marrow progenitors but appears to be imprinted within the remodelled spleen. Crucially, all of these adaptations operate independently of pathogen load and limit the damage caused by malaria parasites in subsequent infections. Acquired immunity to malaria therefore prioritises host fitness over pathogen clearance.
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Affiliation(s)
- Wiebke Nahrendorf
- Institute of Immunology and Infection Research, University of EdinburghEdinburghUnited Kingdom
| | - Alasdair Ivens
- Institute of Immunology and Infection Research, University of EdinburghEdinburghUnited Kingdom
- Centre for Immunity, Infection and Evolution, University of EdinburghEdinburghUnited Kingdom
| | - Philip J Spence
- Institute of Immunology and Infection Research, University of EdinburghEdinburghUnited Kingdom
- Centre for Immunity, Infection and Evolution, University of EdinburghEdinburghUnited Kingdom
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19
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Najafi S, Ghanavat M, Shahrabi S, Gatavizadeh Z, Saki N. The effect of inflammatory factors and their inhibitors on the hematopoietic stem cells fate. Cell Biol Int 2021; 45:900-912. [PMID: 33386770 DOI: 10.1002/cbin.11545] [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: 10/03/2020] [Revised: 12/02/2020] [Accepted: 12/25/2020] [Indexed: 11/12/2022]
Abstract
Inflammatory cytokines exert different effects on hematopoietic stem cells (HSCs), lead to the development of various cell lineages in bone marrow (BM) and are thus a differentiation axis for HSCs. The content used in this article has been obtained by searching PubMed database and Google Scholar search engine of English-language articles (1995-2020) using "Hematopoietic stem cell," "Inflammatory cytokine," "Homeostasis," and "Myelopoiesis." Inflammatory cytokines are involved in the differentiation and proliferation of hematopoietic progenitors to compensate for cellular death due to inflammation. Since each of these cytokines differentiates HSCs into a specific cell line, the difference in the effect of these cytokines on the fate of HSC progenitors can be predicted. Inhibitors of these cytokines can also control the inflammatory process as well as the cells involved in leukemic conditions. In general, inflammatory signaling can specify the dominant cell line in BM to counteract inflammation and leukemic condition via stimulating or inhibiting hematopoietic progenitors. Therefore, detection of the effects of inflammatory cytokines on the differentiation of HSCs can be an appropriate approach to check inflammatory and leukemic conditions and the suppression of these cytokines by their inhibitors allows for control of homeostasis in stressful conditions.
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Affiliation(s)
- Sahar Najafi
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Majid Ghanavat
- Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saied Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | | | - Najmaldin Saki
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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20
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Ghosh D, Stumhofer JS. The spleen: "epicenter" in malaria infection and immunity. J Leukoc Biol 2021; 110:753-769. [PMID: 33464668 PMCID: PMC8518401 DOI: 10.1002/jlb.4ri1020-713r] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/10/2020] [Accepted: 12/11/2020] [Indexed: 12/14/2022] Open
Abstract
The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood‐stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of adaptive immune cells, and the development of protective immunity, all in the face of an intense inflammatory environment. This paper describes how these processes are regulated following infection and recognizes the gaps in our current knowledge, highlighting recent insights from human infections and mouse models.
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Affiliation(s)
- Debopam Ghosh
- Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Jason S Stumhofer
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
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21
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Mesenchymal Stem Cells: A Novel Therapeutic Approach to Enhance Protective Immunomodulation and Erythropoietic Recovery in Malaria. Stem Cell Rev Rep 2021; 17:1993-2002. [PMID: 34117997 PMCID: PMC8196918 DOI: 10.1007/s12015-021-10191-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2021] [Indexed: 02/08/2023]
Abstract
Mesenchymal stem cells (MSCs) are self-renewing, multi-potent heterogeneous stem cells that display strong tissue protective and restorative properties by differentiating into cells of the mesodermal lineages. In addition to multi-lineage differentiation capacity, MSCs play important roles in regulating immune responses, inflammation, and tissue regeneration. MSCs play a role in the outcome of the pathogenesis of several infectious diseases. A unique subset of MSCs accumulates in secondary lymphoid organs during malaria disease progression. These MSCs counteract the capacity of malaria parasites to subvert activating co-stimulatory molecules and to regulate expression of negative co-stimulatory molecules on T lymphocytes. Consequently, MSCs have the capacity to restore the functions of CD34+ haematopoietic cells and CD4+ and CD8+ T cells during malaria infection. These observations suggest that cell-based therapeutics for intervention in malaria may be useful in achieving sterile clearance and preventing disease reactivation. In addition, MSCs provide host protection against malaria by reprogramming erythropoiesis through accelerated formation of colony-forming-units-erythroid (CFU-E) cells in the bone marrow. These findings suggest that MSCs are positive regulators of erythropoiesis, making them attractive targets for treatment of malarial anemia. MSC-based therapies, unlike anti-malarial drugs, display therapeutic effects by targeting a large variety of cellular processes rather than a single pathway. In the present review we focus on these recent research findings and discuss clinical applications of MSC-based therapies for malaria.
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22
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Abstract
Lactic acidosis and hyperlactatemia are common metabolic disturbances in patients with severe malaria. Lactic acidosis causes physiological adverse effects, which can aggravate the outcome of malaria. Despite its clear association with mortality in malaria patients, the etiology of lactic acidosis is not completely understood. In this review, the possible contributors to lactic acidosis and hyperlactatemia in patients with malaria are discussed. Both increased lactate production and impaired lactate clearance may play a role in the pathogenesis of lactic acidosis. The increased lactate production is caused by several factors, including the metabolism of intraerythrocytic Plasmodium parasites, aerobic glycolysis by activated immune cells, and an increase in anaerobic glycolysis in hypoxic cells and tissues as a consequence of parasite sequestration and anemia. Impaired hepatic and renal lactate clearance, caused by underlying liver and kidney disease, might further aggravate hyperlactatemia. Multiple factors thus participate in the etiology of lactic acidosis in malaria, and further investigations are required to fully understand their relative contributions and the consequences of this major metabolic disturbance.
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Affiliation(s)
- Hendrik Possemiers
- Laboratory of Immunoparasitology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, University of Leuven, Belgium
| | - Leen Vandermosten
- Laboratory of Immunoparasitology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, University of Leuven, Belgium
| | - Philippe E. Van den Steen
- Laboratory of Immunoparasitology, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, University of Leuven, Belgium
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23
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Khan N, Downey J, Sanz J, Kaufmann E, Blankenhaus B, Pacis A, Pernet E, Ahmed E, Cardoso S, Nijnik A, Mazer B, Sassetti C, Behr MA, Soares MP, Barreiro LB, Divangahi M. M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity. Cell 2020; 183:752-770.e22. [PMID: 33125891 PMCID: PMC7599081 DOI: 10.1016/j.cell.2020.09.062] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 06/23/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022]
Abstract
A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
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Affiliation(s)
- Nargis Khan
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada
| | - Jeffrey Downey
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada
| | - Joaquin Sanz
- Department of Theoretical Physics, University of Zaragoza, Institute BIFI for Bio-computation and Physics of Complex Systems, University of Zaragoza, Zaragoza, Spain
| | - Eva Kaufmann
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada
| | | | - Alain Pacis
- Department of Medicine, Genetic Section, University of Chicago, Chicago, IL, USA
| | - Erwan Pernet
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada
| | - Eisha Ahmed
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada
| | | | - Anastasia Nijnik
- Department of Physiology, Complex Traits Group, McGill University, Montreal, QC, Canada
| | - Bruce Mazer
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada
| | - Christopher Sassetti
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA
| | - Marcel A Behr
- McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada
| | | | - Luis B Barreiro
- Department of Medicine, Genetic Section, University of Chicago, Chicago, IL, USA
| | - Maziar Divangahi
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada.
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24
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Matsumura T, Takahashi Y. The role of myeloid cells in prevention and control of group A streptococcal infections. BIOSAFETY AND HEALTH 2020. [DOI: 10.1016/j.bsheal.2020.05.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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25
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Gomes AC, Saraiva M, Gomes MS. The bone marrow hematopoietic niche and its adaptation to infection. Semin Cell Dev Biol 2020; 112:37-48. [PMID: 32553581 DOI: 10.1016/j.semcdb.2020.05.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 05/14/2020] [Accepted: 05/19/2020] [Indexed: 12/13/2022]
Abstract
Hematopoiesis is responsible for the formation of all blood cells from hematopoietic stem cells (HSC) in the bone marrow (BM). It is a highly regulated process, in order to adapt its cellular output to changing body requirements. Specific microenvironmental conditions within the BM must exist in order to maintain HSC pluripotency and self-renewal, as well as to ensure appropriate differentiation of progenitor cells towards each hematopoietic lineage. Those conditions were coined "the hematopoietic niche" and their identity in terms of cell types, location and soluble molecular components has been the subject of intense research in the last decades. Infections are one of the environmental challenges to which hematopoiesis must respond, to feed the immune system with functional cell components and compensate for cellular losses. However, how infections impact the bone marrow hematopoietic niche(s) remains elusive and most of the mechanisms involved are still largely unknown. Here, we review the most recent advances on our knowledge on the hematopoietic niche composition and regulation during homeostasis and also on how the niche responds to infectious stress.
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Affiliation(s)
- Ana Cordeiro Gomes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal
| | - Margarida Saraiva
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal
| | - Maria Salomé Gomes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200-135, Porto, Portugal; Departamento de Biologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
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26
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Mouse models of neutropenia reveal progenitor-stage-specific defects. Nature 2020; 582:109-114. [PMID: 32494068 PMCID: PMC8041154 DOI: 10.1038/s41586-020-2227-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 02/24/2020] [Indexed: 02/07/2023]
Abstract
Advances in genetics and sequencing reveal a plethora of disease-associated and disease-causing genetic alterations. Resolving causality between genetics and disease requires generating accurate models for molecular dissection; however, the rapid expansion of single-cell landscapes presents a major challenge to accurate comparisons between mutants and their wild-type equivalents. Here, we generated mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the Growth factor independent-1 (GFI1) transcription factor. To delineate the impact of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes1, aligned mutant cells to their wild-type equivalent and identified differentially expressed genes and epigenetic loci. We find that Gfi1-target genes are altered sequentially, as cells traverse successive states during differentiation. These cell-state-specific insights facilitated genetic rescue of granulocytic specification but not post-commitment defects in innate-immune effector function; underscoring the importance of evaluating the impact of mutations and therapy within each relevant cell state.
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27
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Silva-Filho JL, Lacerda MVG, Recker M, Wassmer SC, Marti M, Costa FTM. Plasmodium vivax in Hematopoietic Niches: Hidden and Dangerous. Trends Parasitol 2020; 36:447-458. [PMID: 32298632 DOI: 10.1016/j.pt.2020.03.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/01/2020] [Accepted: 03/04/2020] [Indexed: 12/31/2022]
Abstract
Estimation of Plasmodium vivax biomass based on circulating biomarkers indicates the existence of a predominant biomass outside of the circulation that is not captured by peripheral parasitemia, in particular in patients with complicated outcomes. A series of recent studies have suggested that the hematopoietic niche of the bone marrow (BM) is a major reservoir for parasite replication and the development of transmission stages. However, significant knowledge gaps remain in our understanding of host-parasite interactions, pathophysiology, and the implications for treatment and diagnosis of such a reservoir. Here, we discuss the current status of this emerging research field in the context of P. vivax.
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Affiliation(s)
- João Luiz Silva-Filho
- Laboratório de Doenças Tropicais - Prof Luiz Jacintho da Silva Instituto de Biologia, Universidade Estadual de Campinas, Campinas, Brazil; Wellcome Center for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| | - Marcus V G Lacerda
- Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil; Instituto Leônidas and Maria Deane, Fiocruz Amazônia, Manaus, Brazil
| | - Mario Recker
- Centre for Mathematics and the Environment, University of Exeter, Penryn Campus, Penryn, UK
| | - Samuel C Wassmer
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK
| | - Matthias Marti
- Wellcome Center for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
| | - Fabio T M Costa
- Laboratório de Doenças Tropicais - Prof Luiz Jacintho da Silva Instituto de Biologia, Universidade Estadual de Campinas, Campinas, Brazil.
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28
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Pérez‐Mazliah D, Ndungu FM, Aye R, Langhorne J. B-cell memory in malaria: Myths and realities. Immunol Rev 2020; 293:57-69. [PMID: 31733075 PMCID: PMC6972598 DOI: 10.1111/imr.12822] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 10/15/2019] [Accepted: 10/24/2019] [Indexed: 12/26/2022]
Abstract
B-cell and antibody responses to Plasmodium spp., the parasite that causes malaria, are critical for control of parasitemia and associated immunopathology. Antibodies also provide protection to reinfection. Long-lasting B-cell memory has been shown to occur in response to Plasmodium spp. in experimental model infections, and in human malaria. However, there are reports that antibody responses to several malaria antigens in young children living with malaria are not similarly long-lived, suggesting a dysfunction in the maintenance of circulating antibodies. Some studies attribute this to the expansion of atypical memory B cells (AMB), which express multiple inhibitory receptors and activation markers, and are hyporesponsive to B-cell receptor (BCR) restimulation in vitro. AMB are also expanded in other chronic infections such as tuberculosis, hepatitis B and C, and HIV, as well as in autoimmunity and old age, highlighting the importance of understanding their role in immunity. Whether AMB are dysfunctional remains controversial, as there are also studies in other infections showing that AMB can produce isotype-switched antibodies and in mouse can contribute to protection against infection. In light of these controversies, we review the most recent literature on either side of the debate and challenge some of the currently held views regarding B-cell responses to Plasmodium infections.
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Affiliation(s)
- Damián Pérez‐Mazliah
- The Francis Crick InstituteLondonUK
- York Biomedical Research InstituteHull York Medical SchoolUniversity of YorkYorkUK
| | | | - Racheal Aye
- Department of Immunology and Infectious DiseaseJohn Curtin School of Medical ResearchThe Australian National UniversityCanberraAustralia
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29
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Matthews H, Noulin F. Unexpected encounter of the parasitic kind. World J Stem Cells 2019; 11:904-919. [PMID: 31768219 PMCID: PMC6851008 DOI: 10.4252/wjsc.v11.i11.904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 08/10/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Both parasitology and stem cell research are important disciplines in their own right. Parasites are a real threat to human health causing a broad spectrum of diseases and significant annual rates morbidity and mortality globally. Stem cell research, on the other hand, focuses on the potential for regenerative medicine for a range of diseases including cancer and regenerative therapies. Though these two topics might appear distant, there are some “unexpected encounters”. In this review, we summarise the various links between parasites and stem cells. First, we discuss how parasites’ own stem cells represent interesting models of regeneration that can be translated to human stem cell regeneration. Second, we explore the interactions between parasites and host stem cells during the course of infection. Third, we investigate from a clinical perspective, how stem cell regeneration can be exploited to help circumvent the damage induced by parasitic infection and its potential to serve as treatment options for parasitic diseases in the future. Finally, we discuss the importance of screening for pathogens during organ transplantation by presenting some clinical cases of parasitic infection following stem cell therapy.
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Affiliation(s)
- Holly Matthews
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
| | - Florian Noulin
- Centre for Applied Entomology and Parasitology, School of Life Sciences, Keele University, Keele ST5 5BG, United Kingdom
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30
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Hirako IC, Assis PA, Galvão-Filho B, Luster AD, Antonelli LR, Gazzinelli RT. Monocyte-derived dendritic cells in malaria. Curr Opin Microbiol 2019; 52:139-150. [PMID: 31542508 DOI: 10.1016/j.mib.2019.08.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 08/03/2019] [Accepted: 08/17/2019] [Indexed: 12/16/2022]
Abstract
The pathogenesis of malaria is a multifactorial syndrome associated with a deleterious inflammatory response that is responsible for many of the clinical manifestations. While dendritic cells (DCs) play a critical role in initiating acquired immunity and host resistance to infection, they also play a pathogenic role in inflammatory diseases. In our recent studies, we found in different rodent malaria models that the monocyte-derived DCs (MO-DCs) become, transiently, a main DC population in spleens and inflamed non-lymphoid organs. These studies suggest that acute infection with Plasmodium berghei promotes the differentiation of splenic monocytes into inflammatory monocytes (iMOs) and thereafter into MO-DCs that play a pathogenic role by promoting inflammation and tissue damage. The recruitment of MO-DCs to the lungs and brain are dependent on expression of CCR4 and CCR5, respectively, and expression of respective chemokine ligands in each organ. Once they reach the target organ the MO-DCs produce the CXCR3 ligands (CXCL9 and CXCL10), recruit CD8+ T cells, and produce toxic metabolites that play an important role in the development of experimental cerebral malaria (ECM) and acute respiratory distress syndrome (ARDS).
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Affiliation(s)
- Isabella C Hirako
- Fundação Oswaldo Cruz - Minas, 30190-002 Belo Horizonte, MG, Brazil; University of Massachusetts Medical School, 01605 Worcester, MA, United States
| | - Patrícia A Assis
- University of Massachusetts Medical School, 01605 Worcester, MA, United States
| | | | - Andrew D Luster
- Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
| | - Lis Rv Antonelli
- Fundação Oswaldo Cruz - Minas, 30190-002 Belo Horizonte, MG, Brazil
| | - Ricardo T Gazzinelli
- Fundação Oswaldo Cruz - Minas, 30190-002 Belo Horizonte, MG, Brazil; University of Massachusetts Medical School, 01605 Worcester, MA, United States; Plataforma de Medicina Translacional, Fundação Oswaldo Cruz, 14049-900, Ribeirão Preto, SP, Brazil.
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31
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Bennett LF, Liao C, Quickel MD, Yeoh BS, Vijay-Kumar M, Hankey-Giblin P, Prabhu KS, Paulson RF. Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C. Sci Signal 2019; 12:12/598/eaap7336. [PMID: 31506384 DOI: 10.1126/scisignal.aap7336] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.
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Affiliation(s)
- Laura F Bennett
- Intercollege Graduate Program in Genetics, Penn State University, University Park, PA 16802, USA.,Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA
| | - Chang Liao
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA.,Graduate Program in Pathobiology, Penn State University, University Park, PA 16802, USA.,Center for Molecular Immunology and Infectious Disease, Penn State University, University Park, PA 16802, USA
| | - Michael D Quickel
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA.,Graduate Program in Pathobiology, Penn State University, University Park, PA 16802, USA.,Clinical and Translational Science Institute, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Beng San Yeoh
- Graduate Program in Molecular, Cellular and Integrative Biosciences, Penn State University, University Park, PA 16802, USA
| | - Matam Vijay-Kumar
- Center for Molecular Immunology and Infectious Disease, Penn State University, University Park, PA 16802, USA.,Graduate Program in Molecular, Cellular and Integrative Biosciences, Penn State University, University Park, PA 16802, USA.,Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA
| | - Pamela Hankey-Giblin
- Intercollege Graduate Program in Genetics, Penn State University, University Park, PA 16802, USA.,Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA.,Graduate Program in Pathobiology, Penn State University, University Park, PA 16802, USA.,Center for Molecular Immunology and Infectious Disease, Penn State University, University Park, PA 16802, USA
| | - K Sandeep Prabhu
- Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA.,Graduate Program in Pathobiology, Penn State University, University Park, PA 16802, USA.,Center for Molecular Immunology and Infectious Disease, Penn State University, University Park, PA 16802, USA.,Graduate Program in Molecular, Cellular and Integrative Biosciences, Penn State University, University Park, PA 16802, USA
| | - Robert F Paulson
- Intercollege Graduate Program in Genetics, Penn State University, University Park, PA 16802, USA. .,Department of Veterinary and Biomedical Sciences, Penn State University, University Park, PA 16802, USA.,Center for Molecular Immunology and Infectious Disease, Penn State University, University Park, PA 16802, USA.,Graduate Program in Molecular, Cellular and Integrative Biosciences, Penn State University, University Park, PA 16802, USA
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32
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Khader SA, Divangahi M, Hanekom W, Hill PC, Maeurer M, Makar KW, Mayer-Barber KD, Mhlanga MM, Nemes E, Schlesinger LS, van Crevel R, Vankayalapati R(K, Xavier RJ, Netea MG. Targeting innate immunity for tuberculosis vaccination. J Clin Invest 2019; 129:3482-3491. [PMID: 31478909 PMCID: PMC6715374 DOI: 10.1172/jci128877] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.
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Affiliation(s)
- Shabaana A. Khader
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA
| | - Maziar Divangahi
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, and Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, Quebec, Canada
| | - Willem Hanekom
- Bill & Melinda Gates Foundation, Seattle, Washington, USA
| | - Philip C. Hill
- Centre for International Health, Department of Preventive and Social Medicine, University of Otago Medical School, Dunedin, New Zealand
| | - Markus Maeurer
- Department of Oncology/Haematology, Krankenhaus Nordwest (KHNW), Frankfurt, Germany
- ImmunoSurgery Unit, Champalimaud Foundation, Lisbon, Portugal
| | - Karen W. Makar
- Bill & Melinda Gates Foundation, Seattle, Washington, USA
| | - Katrin D. Mayer-Barber
- Inflammation and Innate Immunity Unit, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Musa M. Mhlanga
- Division of Chemical Systems & Synthetic Biology, Institute for Infectious Disease & Molecular Medicine (IDM), Faculty of Health Sciences, Department of Integrative Biomedical Sciences, and
| | - Elisa Nemes
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
| | | | - Reinout van Crevel
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
| | - Raman (Krishna) Vankayalapati
- Department of Pulmonary Immunology, Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, Texas, USA
| | - Ramnik J. Xavier
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
- Center for Computational and Integrative Biology and
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
- Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany
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33
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Leung GA, Cool T, Valencia CH, Worthington A, Beaudin AE, Forsberg EC. The lymphoid-associated interleukin 7 receptor (IL7R) regulates tissue-resident macrophage development. Development 2019; 146:146/14/dev176180. [PMID: 31332039 DOI: 10.1242/dev.176180] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/25/2019] [Indexed: 12/13/2022]
Abstract
The discovery of a fetal origin for tissue-resident macrophages (trMacs) has inspired an intense search for the mechanisms underlying their development. Here, we performed in vivo lineage tracing of cells with an expression history of IL7Rα, a marker exclusively associated with the lymphoid lineage in adult hematopoiesis. Surprisingly, we found that Il7r-Cre labeled fetal-derived, adult trMacs. Labeling was almost complete in some tissues and partial in others. The putative progenitors of trMacs, yolk sac (YS) erythromyeloid progenitors, did not express IL7R, and YS hematopoiesis was unperturbed in IL7R-deficient mice. In contrast, tracking of IL7Rα message levels, surface expression, and Il7r-Cre-mediated labeling across fetal development revealed dynamic regulation of Il7r mRNA expression and rapid upregulation of IL7Rα surface protein upon transition from monocyte to macrophage within fetal tissues. Fetal monocyte differentiation in vitro produced IL7R+ macrophages, supporting a direct progenitor-progeny relationship. Additionally, blockade of IL7R function during late gestation specifically impaired the establishment of fetal-derived trMacs in vivo These data provide evidence for a distinct function of IL7Rα in fetal myelopoiesis and identify IL7R as a novel regulator of trMac development.
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Affiliation(s)
- Gabriel A Leung
- Quantitative and Systems Biology Program, University of California-Merced, Merced, CA 95343, USA
| | - Taylor Cool
- Institute for the Biology of Stem Cells, University of California-Santa Cruz, Santa Cruz, CA 95064, USA.,Department of Biological Sciences, San Jose State University, San Jose, CA 95192, USA.,Department of Molecular, Cell, and Developmental Biology, University of California-Santa Cruz, Santa Cruz, CA 95064, USA
| | - Clint H Valencia
- Molecular and Cell Biology Department, School of Natural Sciences, University of California-Merced, Merced, CA 95343, USA
| | - Atesh Worthington
- Institute for the Biology of Stem Cells, University of California-Santa Cruz, Santa Cruz, CA 95064, USA.,Department of Molecular, Cell, and Developmental Biology, University of California-Santa Cruz, Santa Cruz, CA 95064, USA
| | - Anna E Beaudin
- Molecular and Cell Biology Department, School of Natural Sciences, University of California-Merced, Merced, CA 95343, USA
| | - E Camilla Forsberg
- Institute for the Biology of Stem Cells, University of California-Santa Cruz, Santa Cruz, CA 95064, USA .,Department of Biomolecular Engineering, University of California-Santa Cruz, Santa Cruz, CA 95064, USA
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34
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Qin Y, Fang K, Lu N, Hu Y, Tian Z, Zhang C. Interferon gamma inhibits the differentiation of mouse adult liver and bone marrow hematopoietic stem cells by inhibiting the activation of notch signaling. Stem Cell Res Ther 2019; 10:210. [PMID: 31311586 PMCID: PMC6636148 DOI: 10.1186/s13287-019-1311-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 06/18/2019] [Accepted: 06/20/2019] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The paradigm of hematopoietic stem and progenitor cells (HSPCs) has become accepted ever since the discovery of adult mouse liver hematopoietic stem cells and their multipotent characteristics that give rise to all blood cells. However, differences between bone marrow (BM) and liver hematopoietic stem cells and the hematopoietic microenvironment remain poorly understood. In addition, the regulation of the liver hematopoietic system remains unknown. METHODS Clone formation assays were used to confirm that the proliferation of adult mouse liver and bone marrow HSPCs. Model mice with different interferon gamma (IFN-γ) levels and a co-culture system were used to detect the differentiation of liver HSPCs. The γ-secretase inhibitor (GSI) and the JAK/STAT inhibitor ruxolitinib and cell culture assays were used to explore the molecular mechanism by which IFN-γ impairs HSPC proliferation and differentiation. RESULTS The colony-forming activity of liver and bone marrow HSPCs was inhibited by IFN-γ. Model mice with different IFN-γ levels showed that the differentiation of liver HSPCs was impaired by IFN-γ. Using a co-culture system comprising liver HSPCs, we found that IFN-γ inhibited the development of liver hematopoietic stem cells into γδT cells. We then demonstrated that IFN-γ might impair liver HSPC differentiation by inhibiting the activation of the notch signaling via the JAK/STAT signaling pathway. CONCLUSIONS IFN-γ inhibited the proliferation of liver-derived HSPCs. IFN-γ also impaired the differentiation of long-term hematopoietic stem cells (LT-HSCs) into short-term hematopoietic stem cells (ST-HSCs) and multipotent progenitors (MPPs) and the process from LSK (Lineage-Sca-1+c-Kit+) cells to γδT cells. Importantly, we proposed that IFN-γ might inhibit the activation of notch signaling through the JAK/STAT signaling pathway and thus impair the differentiation process of mouse adult liver and BM hematopoietic stem cells.
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Affiliation(s)
- Yuhong Qin
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Keke Fang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Nan Lu
- Institute of Diagnostics, School of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| | - Yuan Hu
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China
| | - Zhigang Tian
- Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, 230026, Anhui, China
| | - Cai Zhang
- Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, Shandong, China.
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35
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Abstract
Ever since hematopoietic stem cells (HSCs) were first identified half a century ago, their differentiation roadmap has been extensively studied. The classical model of hematopoiesis has long held as a dogma that HSCs reside at the top of a hierarchy in which HSCs possess self-renewal capacity and can progressively give rise to all blood lineage cells. However, over the past several years, with advances in single cell technologies, this developmental scheme has been challenged. In this review, we discuss the evidence supporting heterogeneity within HSC and progenitor populations as well as the hierarchical models revised by novel approaches mainly in mouse system. These evolving views provide further understanding of hematopoiesis and highlight the complexity of hematopoietic differentiation.
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36
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Yousefi M, Mamipour M, Sokullu SE, Ghaderi S, Amini H, Rahbarghazi R. Toll-like receptors in the functional orientation of cardiac progenitor cells. J Cell Physiol 2019; 234:19451-19463. [PMID: 31025370 DOI: 10.1002/jcp.28738] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/04/2019] [Accepted: 04/11/2019] [Indexed: 12/17/2022]
Abstract
Cardiac progenitor cells (CPCs) have the potential to differentiate into several cell lineages with the ability to restore in cardiac tissue. Multipotency and self-renewal activity are the crucial characteristics of CPCs. Also, CPCs have promising therapeutic roles in cardiac diseases such as valvular disease, thrombosis, atherosclerosis, congestive heart failure, and cardiac remodeling. Toll-like receptors (TLRs), as the main part of the innate immunity, have a key role in the development and differentiation of immune cells. Some reports are found regarding the effect of TLRs in the maturation of stem cells. This article tried to find the potential role of TLRs in the dynamics of CPCs. By showing possible crosstalk between the TLR signaling pathways and CPCs dynamics, we could achieve a better conception related to TLRs in the regeneration of cardiac tissue.
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Affiliation(s)
- Mohammadreza Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Translational Medicine, Koç University, Istanbul, Turkey
| | - Mina Mamipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Translational Medicine, Koç University, Istanbul, Turkey
| | - Sadiye E Sokullu
- Engineering Sciences, Bioengineering Department, Faculty of Engineering and Architecture, Izmir Katip Celebi University, Izmir, Turkey
| | - Shahrooz Ghaderi
- Department of System Physiology, Ruhr University, Bochum, Germany
| | - Hassan Amini
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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37
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Palomo J, Quesniaux VFJ, Togbe D, Reverchon F, Ryffel B. Unravelling the roles of innate lymphoid cells in cerebral malaria pathogenesis. Parasite Immunol 2019; 40. [PMID: 29117626 DOI: 10.1111/pim.12502] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 10/31/2017] [Indexed: 12/17/2022]
Abstract
Cerebral malaria (CM) is one complication of Plasmodium parasite infection that can lead to strong inflammatory immune responses in the central nervous system (CNS), accompanied by lung inflammation and anaemia. Here, we focus on the role of the innate immune response in experimental cerebral malaria (ECM) caused by blood-stage murine Plasmodium berghei ANKA infection. While T cells are important for ECM pathogenesis, the role of innate lymphoid cells (ILCs) is only emerging. The role of ILCs and non-lymphoid cells, such as neutrophils and platelets, contributing to the host immune response and leading to ECM and human cerebral malaria (HCM) is reviewed.
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Affiliation(s)
- J Palomo
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS, University of Orleans, Orleans-Cedex2, France.,Division of Rheumatology, Departments of Internal Medicine Specialties and of Pathology-Immunology, University of Geneva School of Medicine, Geneva, Switzerland
| | - V F J Quesniaux
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS, University of Orleans, Orleans-Cedex2, France
| | - D Togbe
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS, University of Orleans, Orleans-Cedex2, France.,Artimmune SAS, Orléans, France
| | - F Reverchon
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS, University of Orleans, Orleans-Cedex2, France
| | - B Ryffel
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS, University of Orleans, Orleans-Cedex2, France.,IDM, Medical School, University of Cape Town, Cape Town, Republic of South Africa
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38
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Kumar R, Ng S, Engwerda C. The Role of IL-10 in Malaria: A Double Edged Sword. Front Immunol 2019; 10:229. [PMID: 30809232 PMCID: PMC6379449 DOI: 10.3389/fimmu.2019.00229] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 01/28/2019] [Indexed: 12/11/2022] Open
Abstract
IL-10 produced by CD4+ T cells suppresses inflammation by inhibiting T cell functions and the upstream activities of antigen presenting cells (APCs). IL-10 was first identified in Th2 cells, but has since been described in IFNγ-producing Tbet+ Th1, FoxP3+ CD4+ regulatory T (Treg) and IL-17-producing CD4+ T (Th17) cells, as well as many innate and innate-like immune cell populations. IL-10 production by Th1 cells has emerged as an important mechanism to dampen inflammation in the face of intractable infection, including in African children with malaria. However, although these type I regulatory T (Tr1) cells protect tissue from inflammation, they may also promote disease by suppressing Th1 cell-mediated immunity, thereby allowing infection to persist. IL-10 produced by other immune cells during malaria can also influence disease outcome, but the full impact of this IL-10 production is still unclear. Together, the actions of this potent anti-inflammatory cytokine along with other immunoregulatory mechanisms that emerge following Plasmodium infection represent a potential hurdle for the development of immunity against malaria, whether naturally acquired or vaccine-induced. Recent advances in understanding how IL-10 production is initiated and regulated have revealed new opportunities for manipulating IL-10 for therapeutic advantage. In this review, we will summarize our current knowledge about IL-10 production during malaria and discuss its impact on disease outcome. We will highlight recent advances in our understanding about how IL-10 production by specific immune cell subsets is regulated and consider how this knowledge may be used in drug delivery and vaccination strategies to help eliminate malaria.
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Affiliation(s)
- Rajiv Kumar
- Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, India.,Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
| | - Susanna Ng
- Immunology and Infection Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Christian Engwerda
- Immunology and Infection Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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Wildes TJ, Flores CT, Mitchell DA. Concise Review: Modulating Cancer Immunity with Hematopoietic Stem and Progenitor Cells. Stem Cells 2019; 37:166-175. [PMID: 30353618 PMCID: PMC6368859 DOI: 10.1002/stem.2933] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 09/19/2018] [Accepted: 10/02/2018] [Indexed: 12/17/2022]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are the progenitor cells that can regenerate the entire blood compartment, including the immune system. Recent studies have unearthed considerable immune-modulating potential of these cells. They can migrate through chemotactic gradients, differentiate into functional immune cells, and crosstalk with immune cells during infections, autoimmune diseases, and cancers. Although the primary role of HSPCs during solid malignancies is considered immunosuppressive, recent studies have discovered immune-activating HSPCs and progeny. In this review, we will discuss the recent evidence that HSPCs act as immunomodulators during solid cancers and highlight the future directions of discovery. Stem Cells 2019;37:166-175.
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Affiliation(s)
- Tyler J. Wildes
- University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of NeurosurgeryMcKnight Brain Institute, University of FloridaGainesvilleFloridaUSA
| | - Catherine T. Flores
- University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of NeurosurgeryMcKnight Brain Institute, University of FloridaGainesvilleFloridaUSA
| | - Duane A. Mitchell
- University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of NeurosurgeryMcKnight Brain Institute, University of FloridaGainesvilleFloridaUSA
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40
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Kwon KW, Kim SJ, Kim H, Kim WS, Kang SM, Choi E, Ha SJ, Yoon JH, Shin SJ. IL-15 Generates IFN-γ-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation. Int J Biol Sci 2019; 15:464-480. [PMID: 30745835 PMCID: PMC6367559 DOI: 10.7150/ijbs.25743] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 12/02/2018] [Indexed: 11/23/2022] Open
Abstract
Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-γ-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic characteristics of IFN-γ-producing IL-15-DBMCs and their functional role in the control of intracellular Mycobacterium tuberculosis (Mtb) infection. When comparing the cytokine levels between bone marrow-derived dendritic cells (BMDCs) and IL-15-DBMCs upon stimulation with various TLR agonists, only the CD11cint population of IL-15-DBMCs produced significant levels of IFN-γ, decreased levels of MHC-II, and increased levels of B220. Neither BMDCs nor IL-15-DBMCs were found to express DX5 or NK1.1, which are representative markers for the NK cell lineage and IKDCs. When the CD11cintB220+ population of IL-15-DBMCs was enriched, the Thy1.2+Sca-1+ population showed a marked increase in IFN-γ production. In addition, while depletion of the B220+ and Thy1.2+ populations of IL-15-DBMCs, but not the CD19+ population, inhibited IFN-γ production, enrichment of these cell populations increased IFN-γ. Ultimately, co-culture of sorted IFN-γ-producing B220+Thy1.2+ IL-15-DBMCs with Mtb-infected macrophages resulted in control of the intracellular growth of Mtb via the IFN-γ-nitric oxide axis in a donor cell number-dependent manner. Taken together, the results indicate that IFN-γ-producing IL-15-DBMCs could be redefined as CD11cintB220+Thy1.2+Sca-1+ cells, which phenotypically resemble both IKDCs and ILC1s, and may have therapeutic potential for controlling infectious intracellular bacteria such as Mtb.
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Affiliation(s)
- Kee Woong Kwon
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - So Jeong Kim
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Hongmin Kim
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Woo Sik Kim
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Soon Myung Kang
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Eunsol Choi
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Sang-Jun Ha
- Department of Biochemistry, College of Life Science & Biotechnology, Yonsei University, Seoul, South Korea
| | - Joo-Heon Yoon
- The Airway Mucus Institute, and Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, South Korea
| | - Sung Jae Shin
- Department of Microbiology, Institute for Immunology and Immunological Disease, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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41
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Kaufmann E, Sanz J, Dunn JL, Khan N, Mendonça LE, Pacis A, Tzelepis F, Pernet E, Dumaine A, Grenier JC, Mailhot-Léonard F, Ahmed E, Belle J, Besla R, Mazer B, King IL, Nijnik A, Robbins CS, Barreiro LB, Divangahi M. BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis. Cell 2018; 172:176-190.e19. [PMID: 29328912 DOI: 10.1016/j.cell.2017.12.031] [Citation(s) in RCA: 766] [Impact Index Per Article: 109.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 11/06/2017] [Accepted: 12/19/2017] [Indexed: 12/31/2022]
Abstract
The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
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Affiliation(s)
- Eva Kaufmann
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Joaquin Sanz
- Department of Biochemistry, Faculty of Medicine, Université de Montréal, QC H3T 1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada
| | - Jonathan L Dunn
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Nargis Khan
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Laura E Mendonça
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Alain Pacis
- Department of Biochemistry, Faculty of Medicine, Université de Montréal, QC H3T 1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada
| | - Fanny Tzelepis
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Erwan Pernet
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Anne Dumaine
- Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada
| | | | | | - Eisha Ahmed
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Jad Belle
- Department of Physiology, Complex Traits Group, McGill University, Montreal, QC H3G 0B1, Canada
| | - Rickvinder Besla
- Department of Immunology, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Bruce Mazer
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Irah L King
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada
| | - Anastasia Nijnik
- Department of Physiology, Complex Traits Group, McGill University, Montreal, QC H3G 0B1, Canada
| | - Clinton S Robbins
- Department of Immunology, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Luis B Barreiro
- Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada.
| | - Maziar Divangahi
- Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
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42
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Necroinflammation emerges as a key regulator of hematopoiesis in health and disease. Cell Death Differ 2018; 26:53-67. [PMID: 30242210 DOI: 10.1038/s41418-018-0194-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/05/2018] [Accepted: 08/10/2018] [Indexed: 02/08/2023] Open
Abstract
The hematopoietic system represents an organ system with an exceptional capacity for the production of mature blood cells from a small and mostly quiescent pool of hematopoietic stem cells (HSCs). This extraordinary capacity includes self-renewal but also the propensity to rapidly respond to extrinsic needs, such as acute infections, severe inflammation, and wound healing. In recent years, it became clear that inflammatory signals such as cytokines, chemokine and danger signals from pathogens (PAMPs) or dying cells (DAMPs) impact on HSCs, shaping their proliferation status, lineage bias, and repopulating ability and subsequently increasing the output of mature effector cells. However, inflammatory danger signals negatively impact on the capacity of HSCs to self-renew and to maintain their stem cell capabilities. This is evidenced in conditions of chronic inflammation where bone marrow failure may originate from HSC exhaustion. Even in hematopoietic cancers, inflammatory signals shape the phenotype of the malignant clone as exemplified by necrosome-dependent inflammation elicited during malignant transformation in acute myeloid leukemia. Accordingly, understanding the contribution of inflammatory signals, and specifically necroinflammation, to HSC integrity, HSC long-term functionality, and malignant transformation has attracted substantial research and clinical interest. In this review, we highlight recent developments and open questions at the interplay between inflammation, regulated necrosis, and HSC biology in the context of blood cell development, acute and chronic inflammation, and hematopoietic cancer.
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43
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The Regulatory Role of IFN-γ on the Proliferation and Differentiation of Hematopoietic Stem and Progenitor Cells. Stem Cell Rev Rep 2018; 13:705-712. [PMID: 28852997 DOI: 10.1007/s12015-017-9761-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The replenishment of all blood cell lineages is hierarchically organized by the process of hematopoiesis, which is based on the differentiation pathways of hematopoietic stem and progenitor cells (HSPCs). Due to the ability to balance between self-renewal and differentiation, hematopoietic stem cells (HSCs) can generate the appropriate cell type that is required by the immune system and peripheral blood in response to physiological or pathological conditions. Numerous studies have shown that some proinflammatory cytokines contribute to the regulation of the various hematopoietic compartments. Of these, IFN-γ is a type II interferon primarily produced by T cells and natural killer cells, and plays a major role in the defense against invading pathogens and transformed cancer cells; moreover, a growing amount of research indicates that it exerts negative or positive regulatory effect on hematopoiesis. Although IFN-γ is a widely regarded negative regulator of HSC proliferation, it also participates in some chronic infections or hematological malignancies that induce bone marrow failure. Recent studies have demonstrated unexpected effects of IFN-γ, including the promotion of HSC formation and the stimulation of myelopoiesis. Here, we review the direct and indirect effects of IFN-γ on hematopoiesis, as well as the underlying signaling mechanisms of how IFN-γ modulates the self-renewal, cell cycle entry, and proliferation of HSCs. Next, we describe how IFN-γ affects different stages of the lineage differentiation from HSCs. Finally, we discuss the relationship between IFN-γ and compensatory extramedullary hematopoiesis, as well as some related clinical diseases.
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44
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Li Q, Yang Z, Zhang P, Zhao Y, Yu X, Xue P, Shao Y, Li Q, Jia X, Zhang Q, Cheng L, He M, Zhou Z, Zhang Y. Mercury impact on hematopoietic stem cells is regulated by IFNγ-dependent bone marrow-resident macrophages in mice. Toxicol Lett 2018; 295:54-63. [PMID: 29859861 DOI: 10.1016/j.toxlet.2018.05.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/12/2018] [Accepted: 05/30/2018] [Indexed: 12/21/2022]
Abstract
, but not MeHg, affects HSC through regulating IFNγ-dependent BM-resident macrophages in mice. These findings reveal a previously unknown toxicity of Hg.
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Affiliation(s)
- Qian Li
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Zhengli Yang
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Peng Zhang
- Huzhou Center for Disease Control and Prevention, Zhejiang 313000, China
| | - Yifan Zhao
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Xinchun Yu
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Peng Xue
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Yiming Shao
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Qiang Li
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China; Putuo District Center for Disease Control and Prevention, Shanghai 200333, China
| | - Xiaodong Jia
- Shanghai Municipal Center for Disease Control and Prevention, Shanghai 200336, China
| | - Qi Zhang
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Sciences, Fudan University, Shanghai 200032, China
| | - Longzhen Cheng
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Sciences, Fudan University, Shanghai 200032, China
| | - Miao He
- State Key Laboratory of Medical Neurobiology, Institutes of Brain Sciences, Fudan University, Shanghai 200032, China
| | - Zhijun Zhou
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China
| | - Yubin Zhang
- School of Public Health and Key Laboratory of Public Health Safety, MOE, Fudan University, Shanghai 200032, China.
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Chiba Y, Mizoguchi I, Hasegawa H, Ohashi M, Orii N, Nagai T, Sugahara M, Miyamoto Y, Xu M, Owaki T, Yoshimoto T. Regulation of myelopoiesis by proinflammatory cytokines in infectious diseases. Cell Mol Life Sci 2018; 75:1363-1376. [PMID: 29218601 PMCID: PMC11105622 DOI: 10.1007/s00018-017-2724-5] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 12/19/2022]
Abstract
Hematopoiesis is hierarchically orchestrated by a very small population of hematopoietic stem cells (HSCs) that reside in the bone-marrow niche and are tightly regulated to maintain homeostatic blood production. HSCs are predominantly quiescent, but they enter the cell cycle in response to inflammatory signals evoked by severe systemic infection or injury. Thus, hematopoietic stem and progenitor cells (HSPCs) can be activated by pathogen recognition receptors and proinflammatory cytokines to induce emergency myelopoiesis during infection. This emergency myelopoiesis counterbalances the loss of cells and generates lineage-restricted hematopoietic progenitors, eventually replenishing mature myeloid cells to control the infection. Controlled generation of such signals effectively augments host defense, but dysregulated stimulation by these signals is harmful to HSPCs. Such hematopoietic failure often results in blood disorders including chronic inflammatory diseases and hematological malignancies. Recently, we found that interleukin (IL)-27, one of the IL-6/IL-12 family cytokines, has a unique ability to directly act on HSCs and promote their expansion and differentiation into myeloid progenitors. This process resulted in enhanced production of neutrophils by emergency myelopoiesis during the blood-stage mouse malaria infection. In this review, we summarize recent advances in the regulation of myelopoiesis by proinflammatory cytokines including type I and II interferons, IL-6, IL-27, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and IL-1 in infectious diseases.
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Grants
- a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
- the Private University Strategic Research Based Support Project from the Ministry of Education, Culture, Sports, Science, and Technology, Japan
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Affiliation(s)
- Yukino Chiba
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Izuru Mizoguchi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Hideaki Hasegawa
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Mio Ohashi
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Naoko Orii
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Taro Nagai
- Department of Immunology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Miyaka Sugahara
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
- Institute for Human Life Innovation, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo, 112-8610, Japan
| | - Yasunori Miyamoto
- Institute for Human Life Innovation, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo, 112-8610, Japan
| | - Mingli Xu
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Toshiyuki Owaki
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan
| | - Takayuki Yoshimoto
- Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
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46
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Parigi SM, Czarnewski P, Das S, Steeg C, Brockmann L, Fernandez-Gaitero S, Yman V, Forkel M, Höög C, Mjösberg J, Westerberg L, Färnert A, Huber S, Jacobs T, Villablanca EJ. Flt3 ligand expands bona fide innate lymphoid cell precursors in vivo. Sci Rep 2018; 8:154. [PMID: 29317685 PMCID: PMC5760642 DOI: 10.1038/s41598-017-18283-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 12/08/2017] [Indexed: 12/20/2022] Open
Abstract
A common helper-like innate lymphoid precursor (CHILP) restricted to the innate lymphoid cells (ILC) lineage has been recently characterized. While specific requirements of transcription factors for CHILPs development has been partially described, their ability to sense cytokines and react to peripheral inflammation remains unaddressed. Here, we found that systemic increase in Flt3L levels correlated with the expansion of Lineage (Lin)negα4β7+ precursors in the adult murine bone marrow. Expanded Linnegα4β7+ precursors were bona fide CHILPs as seen by their ability to differentiate into all helper ILCs subsets but cNK in vivo. Interestingly, Flt3L-expanded CHILPs transferred into lymphopenic mice preferentially reconstituted the small intestine. While we did not observe changes in serum Flt3L during DSS-induced colitis in mice or plasma from inflammatory bowel disease (IBD) patients, elevated Flt3L levels were detected in acute malaria patients. Interestingly, while CHILP numbers were stable during the course of DSS-induced colitis, they expanded following increased serum Flt3L levels in malaria-infected mice, hence suggesting a role of the Flt3L-ILC axis in malaria. Collectively, our results indicate that Flt3L expands CHILPs in the bone marrow, which might be associated with specific inflammatory conditions.
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Affiliation(s)
- Sara M Parigi
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Paulo Czarnewski
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Srustidhar Das
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Christiane Steeg
- Department of Immunology, Bernhard-Nocht-Institut for Tropical Medicine, Hamburg, Germany
| | - Leonie Brockmann
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sara Fernandez-Gaitero
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Victor Yman
- Unit of Infectious Diseases, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden
| | - Marianne Forkel
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Charlotte Höög
- Unit for Inflammation, Gastroenterology and Rheumathology, Department of Medicine, Huddinge, Sweden
| | - Jenny Mjösberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Lisa Westerberg
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Anna Färnert
- Unit of Infectious Diseases, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Samuel Huber
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Jacobs
- Department of Immunology, Bernhard-Nocht-Institut for Tropical Medicine, Hamburg, Germany
| | - Eduardo J Villablanca
- Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.
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Ghosh D, Brown SL, Stumhofer JS. IL-17 Promotes Differentiation of Splenic LSK - Lymphoid Progenitors into B Cells following Plasmodium yoelii Infection. THE JOURNAL OF IMMUNOLOGY 2017; 199:1783-1795. [PMID: 28733485 DOI: 10.4049/jimmunol.1601972] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 06/28/2017] [Indexed: 01/01/2023]
Abstract
Lineage-Sca-1+c-Kit- (LSK-) cells are a lymphoid progenitor population that expands in the spleen and preferentially differentiates into mature B cells in response to Plasmodium yoelii infection in mice. Furthermore, LSK- derived B cells can subsequently contribute to the ongoing immune response through the generation of parasite-specific Ab-secreting cells, as well as germinal center and memory B cells. However, the factors that promote their differentiation into B cells in the spleen postinfection are not defined. In this article, we show that LSK- cells produce the cytokine IL-17 in response to Plasmodium infection. Using Il-17ra-/- mice, IL-17R signaling in cells other than LSK- cells was found to support their differentiation into B cells. Moreover, primary splenic stromal cells grown in the presence of IL-17 enhanced the production of CXCL12, a chemokine associated with B cell development in the bone marrow, by a population of IL-17RA-expressing podoplanin+CD31- stromal cells, a profile associated with fibroblastic reticular cells. Subsequent blockade of CXCL12 in vitro reduced differentiation of LSK- cells into B cells, supporting a direct role for this chemokine in this process. Immunofluorescence indicated that podoplanin+ stromal cells in the red pulp were the primary producers of CXCL12 after P. yoelii infection. Furthermore, podoplanin staining on stromal cells was more diffuse, and CXCL12 staining was dramatically reduced in Il-17ra-/- mice postinfection. Together, these results identify a distinct pathway that supports lymphoid development in the spleen during acute Plasmodium infection.
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Affiliation(s)
- Debopam Ghosh
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
| | - Susie L Brown
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
| | - Jason S Stumhofer
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
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48
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TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis. PLoS Pathog 2017; 13:e1006465. [PMID: 28671989 PMCID: PMC5510901 DOI: 10.1371/journal.ppat.1006465] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 07/14/2017] [Accepted: 06/12/2017] [Indexed: 12/12/2022] Open
Abstract
Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naïve mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150+ CD34- CD48- cells) in bone marrow (BM) are quiescent, we found that during Leishmania donovani infection most LT-HSCs had entered cell cycle. Loss of quiescence correlated with a reduced self-renewal capacity and functional exhaustion, as measured by serial transfer. Quiescent LT-HSCs were maintained in infected RAG2 KO mice, but lost following adoptive transfer of IFNγ-sufficient but not IFNγ-deficient CD4+ T cells. Using mixed BM chimeras, we established that IFNγ and TNF signalling pathways converge at the level of CD4+ T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFNγ+CD4+ T cells that promote the irreversible loss of BM function. These findings provide new insights into the pathogenic potential of CD4+ T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously. Visceral leishmaniasis (VL) is a chronic often fatal disease caused by the protozoan parasites Leishmania donovani and L. infantum. Progressive disease in humans and in animal models is associated with parasite replication at systemic sites, including the bone marrow (BM) and results in significant changes in hematological profile. The mechanisms underlying hematologic dysregulation during infection are largely unknown. Using a panel of stem cell markers, we characterized murine haematopoietic stem and progenitor cells in the BM over the course of L. donovani-infection in C57BL/6 (B6) mice. Most long-term hematopoietic stem cells (LT-HSCs) in naïve mice are found in a quiescent state, representing cells with the highest degree of reconstitution potential. In contrast, during L. donovani infection, most LT-HSCs had entered cell-cycle and this correlated with a reduced potential to engraft into syngeneic recipients. HSC exhaustion and other alterations in the hematopoietic compartment did not occur in infected immunodeficient mice, but adoptive transfer of IFNγ-sufficient CD4+ T cells restored this phenotype. Using mixed BM chimeras, we established that IFNγ signalling and TNF signalling pathways converge at the level of BM CD4+ T cells, with intrinsic TNF signalling being critical for the expansion / differentiation of CD4+ T cells that are responsible for HSC exhaustion. Contrary to commonly held views, in the setting of experimental visceral leishmaniasis neither IFNγ nor TNF signalling in HSCs was required for their functional exhaustion. Hence, pro-inflammatory cytokines commonly associated with host protection in leishmaniasis and many other infectious diseases can also drive the development of pathogenic CD4+ T cells that cause long term irreversible alterations in HSC function.
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49
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Fontana MF, de Melo GL, Anidi C, Hamburger R, Kim CY, Lee SY, Pham J, Kim CC. Macrophage Colony Stimulating Factor Derived from CD4+ T Cells Contributes to Control of a Blood-Borne Infection. PLoS Pathog 2016; 12:e1006046. [PMID: 27923070 PMCID: PMC5140069 DOI: 10.1371/journal.ppat.1006046] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 11/07/2016] [Indexed: 12/18/2022] Open
Abstract
Dynamic regulation of leukocyte population size and activation state is crucial for an effective immune response. In malaria, Plasmodium parasites elicit robust host expansion of macrophages and monocytes, but the underlying mechanisms remain unclear. Here we show that myeloid expansion during P. chabaudi infection is dependent upon both CD4+ T cells and the cytokine Macrophage Colony Stimulating Factor (MCSF). Single-cell RNA-Seq analysis on antigen-experienced T cells revealed robust expression of Csf1, the gene encoding MCSF, in a sub-population of CD4+ T cells with distinct transcriptional and surface phenotypes. Selective deletion of Csf1 in CD4+ cells during P. chabaudi infection diminished proliferation and activation of certain myeloid subsets, most notably lymph node-resident CD169+ macrophages, and resulted in increased parasite burden and impaired recovery of infected mice. Depletion of CD169+ macrophages during infection also led to increased parasitemia and significant host mortality, confirming a previously unappreciated role for these cells in control of P. chabaudi. This work establishes the CD4+ T cell as a physiologically relevant source of MCSF in vivo; probes the complexity of the CD4+ T cell response during type 1 infection; and delineates a novel mechanism by which T helper cells regulate myeloid cells to limit growth of a blood-borne intracellular pathogen.
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Affiliation(s)
- Mary F. Fontana
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
- * E-mail: (MFF); (CCK)
| | - Gabrielly L. de Melo
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
| | - Chioma Anidi
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
| | - Rebecca Hamburger
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
| | - Chris Y. Kim
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
| | - So Youn Lee
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
| | - Jennifer Pham
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
| | - Charles C. Kim
- Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
- * E-mail: (MFF); (CCK)
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50
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Wilmore JR, Maue AC, Rochford R. Plasmodium chabaudi infection induces AID expression in transitional and marginal zone B cells. IMMUNITY INFLAMMATION AND DISEASE 2016; 4:497-505. [PMID: 27980783 PMCID: PMC5134720 DOI: 10.1002/iid3.134] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 08/31/2016] [Accepted: 09/30/2016] [Indexed: 11/25/2022]
Abstract
Introduction Endemic Burkitt's lymphoma (eBL) is associated with Epstein–Barr virus and repeated malaria infections. A defining feature of eBL is the translocation of the c‐myc oncogene to the control of the immunoglobulin promoter. Activation‐induced cytidine deaminase (AID) has been shown to be critical for this translocation. Malaria infection induces AID in germinal center B cells, but whether malaria infection more broadly affects AID activation in extrafollicular B cells is unknown. Methods We either stimulated purified B cells from AID‐green fluorescence protein (GFP) reporter mice or infected AID‐GFP mice with Plasmodium chabaudi, AID fluorescence was monitored in B cell subsets by flow cytometry. Results In vitro analysis of B cells from these mice revealed that CpG (a Toll‐like receptor 9 ligand) was a potent inducer of AID in both mature and immature B cell subsets. Infection of AID‐GFP mice with Plasmodium chabaudi demonstrated that AID expression occurs in transitional and marginal zone B cells during acute malaria infection. Transitional B cells were also capable of differentiating into antibody secreting cells when stimulated in vitro with CpG when isolated from a P. chabaudi‐infected mouse. Conclusions These data suggest that P. chabaudi is capable of inducing AID expression in B cell subsets that do not participate in the germinal center reaction, suggesting an alternative role for malaria in the etiology of eBL.
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Affiliation(s)
- Joel R Wilmore
- Department of Microbiology and Immunology SUNY Upstate Medical University Syracuse New York USA
| | - Alexander C Maue
- Department of Microbiology and Immunology SUNY Upstate Medical University Syracuse New York USA
| | - Rosemary Rochford
- Department of Microbiology and ImmunologySUNY Upstate Medical UniversitySyracuseNew YorkUSA; Department of Immunology and MicrobiologyUniversity of ColoradoAuroraColoradoUSA
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