Symbiotic gut commensal bacteria act as host cathepsin S activity regulators

Steimle, Alex; Gronbach, Kerstin; Beifuss, Brigitte; Schäfer, Andrea; Harmening, Robin; Bender, Annika; Maerz, Jan Kevin; Lange, Anna; Michaelis, Lena; Maurer, Andreas; Menz, Sarah; McCoy, Kathy D.; Autenrieth, Ingo B.; Kalbacher, Hubert; Frick, Julia-Stefanie

doi:10.1016/j.jaut.2016.07.009

Cited by 27 publications

(38 citation statements)

References 49 publications

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“…In order to show that B cells are activated and differentiated upon the MAMP recognition via TLRs and that the activation level is dependent on the immunogenicity of encountered microbes, B cells isolated from wild type (WT) and TLR2 −/− × TLR4 −/− (KO) mice were stimulated with two different immunogenic bacteria: B. vulgatus mpk and E. coli mpk (66)(67)(68)(69).…”

Section: B Cell Activation and Maturation Via Strong Immunogenic E Cmentioning

confidence: 99%

“…We primarily focused on the maturation of differentiated CD11c + bone marrow-derived dendritic cells cocultured with bacteria-stimulated B cells ( Figure 3A). Interaction of immature DCs (iDCs) with MAMPs (e.g., Lipopolysaccharide, LPS) results in DC maturation characterized by an enhanced expression of MHC-II, CD40, CD80, and CD86 and increased secretion of TNFα (61,68,69,71). Activated DCs, as professional APCs, are responsible for a robust immune response via antigenrecognition, -processing, and -presentation resulting in a proper activation of T cells (72,73).…”

Section: E Coli-stimulated B Cells Inhibit DC Activation and Maturationmentioning

confidence: 99%

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Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

et al. 2020

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B cells fulfill multifaceted functions that influence immune responses during health and disease. In autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, depletion of functional B cells results in an aggravation of disease in humans and respective mouse models. This could be due to a lack of a pivotal B cell subpopulation: regulatory B cells (Bregs). Although Bregs represent only a small proportion of all immune cells, they exhibit critical properties in regulating immune responses, thus contributing to the maintenance of immune homeostasis in healthy individuals. In this study, we report that the induction of Bregs is differentially triggered by the immunogenicity of the host microbiota. In comparative experiments with low immunogenic Bacteroides vulgatus and strong immunogenic Escherichia coli, we found that the induction and longevity of Bregs depend on strong Toll-like receptor activation mediated by antigens of strong immunogenic commensals. The potent B cell stimulation via E. coli led to a pronounced expression of suppressive molecules on the B cell surface and an increased production of anti-inflammatory cytokines like interleukin-10. These bacteria-primed Bregs were capable of efficiently inhibiting the maturation and function of dendritic cells (DCs), preventing the proliferation and polarization of T helper (Th)1 and Th17 cells while simultaneously promoting Th2 cell differentiation in vitro. In addition, Bregs facilitated the development of regulatory T cells (Tregs) resulting in a possible feedback cooperation to establish immune homeostasis. Moreover, the colonization of germfree wild type mice with E. coli but not B. vulgatus significantly reduced intestinal inflammatory processes in dextran sulfate sodium (DSS)-induced colitis associated with an increase induction of immune suppressive Bregs. The quantity of Bregs directly correlated with the severity of inflammation. These findings may provide new insights and therapeutic approaches for B cell-controlled treatments of microbiota-driven autoimmune disease.

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Section: B Cell Activation and Maturation Via Strong Immunogenic E Cmentioning

confidence: 99%

Section: E Coli-stimulated B Cells Inhibit DC Activation and Maturationmentioning

confidence: 99%

Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

et al. 2020

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“…Cystatin C could regulate various immune responses by either enhancement of host defenses as for parasite elimination, or suppression of host immunity as for autoimmune disease treatments . Our findings that cystatin C differentially affected BMDC function help to resolve the paradox of these reported cases, and suggest that different disease settings might render cystatin C to impact on the different functional aspects of DCs in terms of phagocytosis of foreign antigen, stimulation of T‐cell proliferation or direction of T‐cell differentiation, based on certain cellular environment.…”

Section: Discussionmentioning

confidence: 72%

“…Consistent with their defective T-cell stimulating capacity, the cystatin C-pretreated BMDCs were found to have decreased expression of MHC-II (Figure 3c). Although it has long, 24,25 and more recently, 26 been reported that cystatin C can inhibit the cleavage of MHC-II molecules by cathepsin S to reduce the expression of MHC-II molecules on the DC surface, others have demonstrated that cystatin C was not necessary for the cathepsin S-mediated MHC-II processing and antigen presentation in mouse splenic DCs, 27 or in human-cultured DCs. 23,28 In searching for the other intracellular molecules that might also be subjected to cystatin C regulation, we found in the cystatin C-overexpressing DCs a decreased expression of H2-DM, one of the class II-like chaperone molecules catalyzing the MHC-II maturation and antigen presentation by exchange of class II-associated invariant chain peptide fragment from MHC-II groove for an antigen peptide.…”

Section: Discussionmentioning

confidence: 99%

Cystatin C regulates major histocompatibility complex‐II–peptide presentation and extracellular signal‐regulated kinase‐dependent polarizing cytokine production by bone marrow‐derived dendritic cells

Zhang

Lee

et al. 2019

Immunol Cell Biol

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Cystatin C is a ubiquitously expressed cysteine protease inhibitor that protects cells from either improper hydrolysis by endogenous proteases or pathogen growth/virulence by exogenous proteases. Although commonly used as a serum biomarker for evaluating renal function, cystatin C is associated with many immunological disorders under various pathophysiological conditions. How cystatin C affects immune cells, especially dendritic cells (DCs), however, is far from clear. In this study, we found that pharmacological treatment with or genetic overexpression of cystatin C in bone marrow‐derived DCs (BMDCs) reduced their capacity to stimulate CD4+ T‐cell proliferation, despite increased antigen uptake. This reduced capacity corresponded with reduced major histocompatibility complex‐II presentation owing to diminished levels of the chaperon H2‐DM in BMDCs. Instead of promoting proliferation, cystatin C promoted skewing of T cells toward proinflammatory T‐helper (Th)1/Th17 differentiation. This was mediated by augmented extracellular signal‐regulated kinase 1/2 mitogen‐activated protein kinase phosphorylation in BMDCs, leading to secretion of polarizing cytokines, which in turn led to the Th deviation. Collectively, our study explained the cellular and molecular basis of how this protease inhibitor can regulate immune responses, namely by affecting BMDCs and their cytokine pathway. Our results might open up an avenue for the development of therapeutic agents for the treatment of cystatin C‐related immunological diseases.

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“…LPS is composed of hydrophilic O-antigen polysaccharides and an amphipathic lipid A anchor which is incorporated into the outer bacterial cell membrane. Lipid A, the bioactive centre of LPS, is considered to be an archetypal microbe-associated molecular pattern (MAMP) molecule [6].…”

Section: Introductionmentioning

confidence: 99%

Subgingival lipid A profile and endotoxin activity in periodontal health and disease

et al. 2018

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Symbiotic gut commensal bacteria act as host cathepsin S activity regulators

Cited by 27 publications

References 49 publications

Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

Bacterial Immunogenicity Is Critical for the Induction of Regulatory B Cells in Suppressing Inflammatory Immune Responses

Cystatin C regulates major histocompatibility complex‐II–peptide presentation and extracellular signal‐regulated kinase‐dependent polarizing cytokine production by bone marrow‐derived dendritic cells

Subgingival lipid A profile and endotoxin activity in periodontal health and disease

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