Abstract
C-type lectin receptors (CLRs) are pattern recognition receptors that are crucial in the innate immune response. The gastrointestinal tract contributes significantly to the maintenance of immune homeostasis; it is the shelter for billions of microorganisms including many genera of Lactobacillus sp. Previously, it was shown that host-CLR interactions with gut microbiota play a crucial role in this context. The Macrophage-inducible C-type lectin (Mincle) is a Syk-coupled CLR that contributes to sensing of mucosa-associated commensals. In this study, we identified Mincle as a receptor for the Surface (S)-layer of the probiotic bacteria Lactobacillus brevis modulating GM-CSF bone marrow-derived cells (BMDCs) functions. We found that the S-layer/Mincle interaction led to a balanced cytokine response in BMDCs by triggering the release of both pro- and anti-inflammatory cytokines. In contrast, BMDCs derived from Mincle−/−, CARD9−/− or conditional Syk−/− mice failed to maintain this balance, thus leading to an increased production of the pro-inflammatory cytokines TNF and IL-6, whereas the levels of the anti-inflammatory cytokines IL-10 and TGF-β were markedly decreased. Importantly, this was accompanied by an altered CD4+ T cell priming capacity of Mincle−/− BMDCs resulting in an increased CD4+ T cell IFN-γ production upon stimulation with L. brevis S-layer. Our results contribute to the understanding of how commensal bacteria regulate antigen-presenting cell (APC) functions and highlight the importance of the Mincle/Syk/Card9 axis in APCs as a key factor in host-microbiota interactions.
Highlights
The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are collectively referred to as the gut microbiota [1]
S-layer proteins were extracted from overnight cultures of Lactobacillus brevis (L. brevis) ATCC 14869 bacteria grown in MRS broth at 32◦C and 5% CO2 by using a two-step LiCl extraction; first, with 1 M LiCl to release S-layer associated proteins (SLAP), and with 6 M LiCl [35]
Since it was previously shown that Macrophageinducible C-type lectin (Mincle) recognizes ligands in a Ca2+dependent fashion [41], we determined whether the binding of Mincle-hFc to the L. brevis S-layer was mediated in a Ca2+-dependent manner
Summary
The intestinal tract of mammals is colonized by a large number of microorganisms including trillions of bacteria that are collectively referred to as the gut microbiota [1]. These indigenous microorganisms have co-evolved with their host in a symbiotic relationship [2]. The gut microbiome impacts host immunity by influencing the release of pro- and anti-inflammatory cytokines [4], release of metabolites [5], and by modulating functions of antigen-presenting cells, including dendritic cells (DCs) [6, 7]. In addition to local effects in the intestine, gut microbiota influences host immune responses at extra-intestinal distant sites such as the brain, bone marrow, and lung [12,13,14,15]
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