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Costa DVS, Moura-Neto V, Bolick DT, Guerrant RL, Fawad JA, Shin JH, Medeiros PHQS, Ledwaba SE, Kolling GL, Martins CS, Venkataraman V, Warren CA, Brito GAC. S100B Inhibition Attenuates Intestinal Damage and Diarrhea Severity During Clostridioides difficile Infection by Modulating Inflammatory Response. Front Cell Infect Microbiol 2021; 11:739874. [PMID: 34568098 PMCID: PMC8461106 DOI: 10.3389/fcimb.2021.739874] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
The involvement of the enteric nervous system, which is a source of S100B, in Clostridioides difficile (C. difficile) infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in C. difficile toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from C. difficile-infected mice. To investigate the role of S100B signaling in IL-6 expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from C. difficile-infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated S100B-mediated IL-6 expression via activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by C. difficile toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.
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Affiliation(s)
- Deiziane V S Costa
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.,Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States.,Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Vivaldo Moura-Neto
- Paulo Niemeyer Brain Institute, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil
| | - David T Bolick
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Richard L Guerrant
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Jibraan A Fawad
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Jae H Shin
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Pedro H Q S Medeiros
- Department of Microbiology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Solanka E Ledwaba
- Department of Biochemistry and Microbiology, Faculty of Science, Engineering and Agriculture, University of Venda, Thohoyandou, South Africa
| | - Glynis L Kolling
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Conceição S Martins
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Venkat Venkataraman
- Department of Cell Biology and Neuroscience, Rowan University School of Osteopathic Medicine, Stratford, NJ, United States.,Department of Rehabilitation Medicine, Rowan University School of Osteopathic Medicine, Stratford, NJ, United States
| | - Cirle A Warren
- Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, United States
| | - Gerly A C Brito
- Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil.,Department of Morphology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
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Michetti F, D'Ambrosi N, Toesca A, Puglisi MA, Serrano A, Marchese E, Corvino V, Geloso MC. The S100B story: from biomarker to active factor in neural injury. J Neurochem 2018; 148:168-187. [DOI: 10.1111/jnc.14574] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 07/19/2018] [Accepted: 08/15/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Fabrizio Michetti
- Institute of Anatomy and Cell Biology; Università Cattolica del Sacro Cuore; Rome Italy
- IRCCS San Raffaele Scientific Institute; Università Vita-Salute San Raffaele; Milan Italy
| | - Nadia D'Ambrosi
- Department of Biology; Università degli Studi di Roma Tor Vergata; Rome Italy
| | - Amelia Toesca
- Institute of Anatomy and Cell Biology; Università Cattolica del Sacro Cuore; Rome Italy
| | | | - Alessia Serrano
- Institute of Anatomy and Cell Biology; Università Cattolica del Sacro Cuore; Rome Italy
| | - Elisa Marchese
- Institute of Anatomy and Cell Biology; Università Cattolica del Sacro Cuore; Rome Italy
| | - Valentina Corvino
- Institute of Anatomy and Cell Biology; Università Cattolica del Sacro Cuore; Rome Italy
| | - Maria Concetta Geloso
- Institute of Anatomy and Cell Biology; Università Cattolica del Sacro Cuore; Rome Italy
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Chow AK, Gulbransen BD. Potential roles of enteric glia in bridging neuroimmune communication in the gut. Am J Physiol Gastrointest Liver Physiol 2017; 312:G145-G152. [PMID: 28039160 PMCID: PMC5338608 DOI: 10.1152/ajpgi.00384.2016] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/18/2016] [Accepted: 12/21/2016] [Indexed: 01/31/2023]
Abstract
The enteric nervous system (ENS) is a network of neurons and glia that controls ongoing gastrointestinal (GI) functions. Damage or injury to the ENS can lead to functional GI disorders. Current data support the conclusion that many functional GI disorders are caused by an imbalance between gut microbes and the immune system, but how the ENS is involved in these interactions is less understood. Because of the proximity of the ENS to bacteria and other foreign antigens in the GI tract, it is important to prevent the passage of these antigens through the GI epithelium. If any foreign compounds manage to pass through the GI epithelium, an immune response is triggered to prevent injury to the ENS and underlying structures. However, careful modulation of the inflammatory response is required to allow for adequate elimination of foreign antigens while avoiding inappropriate overactivation of the immune system as in autoimmune disorders. Enteric neurons and glial cells are capable of performing these immunomodulatory functions to provide adequate protection to the ENS. We review recent studies examining the interactions between the ENS and the immune system, with specific focus on enteric glial cells and their ability to modulate inflammation in the ENS.
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Affiliation(s)
- Aaron K. Chow
- 1Department of Physiology, Michigan State University, East Lansing, Michigan; and
| | - Brian D. Gulbransen
- 1Department of Physiology, Michigan State University, East Lansing, Michigan; and ,2Neuroscience Program, Michigan State University, East Lansing, Michigan
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da Cunha Franceschi R, Nardin P, Machado CV, Tortorelli LS, Martinez-Pereira MA, Zanotto C, Gonçalves CA, Zancan DM. Enteric glial reactivity to systemic LPS administration: Changes in GFAP and S100B protein. Neurosci Res 2017; 119:15-23. [PMID: 28063977 DOI: 10.1016/j.neures.2016.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/29/2016] [Accepted: 12/27/2016] [Indexed: 02/07/2023]
Abstract
Lipopolysaccharide (LPS) is used to induce inflammation and promotes nervous system activation. Different regions of the brain present heterogeneous glial responses; thus, in order to verify whether systemic LPS-induced inflammation affects the enteric glia differently across the intestinal segments, we evaluated the expressions of two glial activity markers, GFAP and S100B protein, in different intestine segments, at 1h, 24h and 7days after acute systemic LPS administration (0.25 or 2.5mgkg-1) in rats. Histological inflammatory analysis indicated that the cecum was most affected when compared to the duodenum and proximal colon at the highest doses of LPS. LPS induced an increased S100B content after 24h in all three regions, which decreased at 7days after the highest dose in all regions. Moreover, at 24h, this dose of LPS increased ex-vivo S100B secretion only in the cecum. The highest dose of LPS also increased GFAP in all regions at 24h, but earlier in the cecum, where LPS-induced enteric S100B and GFAP alterations were dependent on dose, time and intestine region. No associated changes in serum S100B were observed. Our results indicate heterogeneous enteric glial responses to inflammatory insult, as observed in distinct brain areas.
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Affiliation(s)
- Raphaela da Cunha Franceschi
- Laboratory of Comparative Neurobiology, Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Graduate Program in Neuroscience, ICBS, UFRGS, Brazil
| | - Patrícia Nardin
- Laboratory of Calcium-Binding Proteins, Department of Biochemistry, ICBS, UFRGS, Brazil
| | - Clivia Valle Machado
- Laboratory of Comparative Neurobiology, Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Graduate Program in Neuroscience, ICBS, UFRGS, Brazil
| | | | | | - Caroline Zanotto
- Laboratory of Calcium-Binding Proteins, Department of Biochemistry, ICBS, UFRGS, Brazil
| | - Carlos-Alberto Gonçalves
- Graduate Program in Neuroscience, ICBS, UFRGS, Brazil; Laboratory of Calcium-Binding Proteins, Department of Biochemistry, ICBS, UFRGS, Brazil.
| | - Denise Maria Zancan
- Laboratory of Comparative Neurobiology, Department of Physiology, Institute of Basic Health Sciences (ICBS), Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Graduate Program in Neuroscience, ICBS, UFRGS, Brazil
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Araújo EJDA, Zaniolo LM, Vicentino SL, Góis MB, Zanoni JN, Silva AVD, Sant’Ana DDMG. Toxoplasma gondii causes death and plastic alteration in the jejunal myenteric plexus. World J Gastroenterol 2015; 21:4829-4839. [PMID: 25944996 PMCID: PMC4408455 DOI: 10.3748/wjg.v21.i16.4829] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 01/01/2015] [Accepted: 01/30/2015] [Indexed: 02/07/2023] Open
Abstract
AIM: To assess the effects of ME-49 Toxoplasma gondii (T. gondii) strain infection on the myenteric plexus and external muscle of the jejunum in rats.
METHODS: Thirty rats were distributed into two groups: the control group (CG) (n = 15) received 1 mL of saline solution orally, and the infected group (IG) (n = 15) inoculated with 1 mL of saline solution containing 500 oocysts of M-49 T. gondii strain orally. After 36 d of infection, the rats were euthanized. Infection with T. gondii was confirmed by blood samples collected from all rats at the beginning and end of the experiment. The jejunum of five animals was removed and submitted to routine histological processing (paraffin) for analysis of external muscle thickness. The remaining jejunum from the others animals was used to analyze the general population and the NADH-diaphorase, VIPergic and nitrergic subpopulations of myenteric neurons; and the enteric glial cells (S100-IR).
RESULTS: Serological analysis showed that animals from the IG were infected with the parasite. Hypertrophy affecting jejunal muscle thickness was observed in the IG rats (77.02 ± 42.71) in relation to the CG (51.40 ± 12.34), P < 0.05. In addition, 31.2% of the total number of myenteric neurons died (CG: 39839.3 ± 5362.3; IG: 26766.6 ± 2177.6; P < 0.05); hyperplasia of nitrergic myenteric neurons was observed (CG: 7959.0 ± 1290.4; IG: 10893.0 ± 1156.3; P < 0.05); general hypertrophy of the cell body in the remaining myenteric neurons was noted [CG: 232.5 (187.2-286.0); IG: 248.2 (204.4-293.0); P < 0.05]; hypertrophy of the smallest varicosities containing VIP neurotransmitter was seen (CG: 0.46 ± 0.10; IG: 0.80 ± 0.16; P < 0.05) and a reduction of 25.3% in enteric glia cells (CG: 12.64 ± 1.27; IG: 10.09 ± 2.10; P < 0.05) was observed in the infected rats.
CONCLUSION: It was concluded that infection with oocysts of ME-49 T. gondii strain caused quantitative and plastic alterations in the myenteric plexus of the jejunum in rats.
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