Gut-derived microbial antigens trigger the innate immune system during acute liver injury. During recovery, regulatory immunity plays a role in suppressing inflammation; however, the precise mechanism underlying this process remains obscure. Here, we find that recruitment of immune-regulatory classical dendritic cells (cDCs) is crucial for liver tolerance in concanavalin A-induced acute liver injury. Acute liver injury resulted in enrichment of commensal Lactobacillus in the gut. Notably, Lactobacillus activated IL-22 production by gut innate lymphoid cells and raised systemic IL-22 levels. Gut-derived IL-22 enhanced mucosal barrier function and promoted the recruitment of regulatory cDCs to the liver. These cDCs produced IL-10 and TGF-β through TLR9 activation, preventing further liver inflammation. Collectively, our results indicate that beneficial gut microbes influence tolerogenic immune responses in the liver. Therefore, modulation of the gut microbiota might be a potential option to regulate liver tolerance.

Cellular metabolic state and individual metabolites have been reported to regulate the functional phenotype of immune cells. Cytokine production by regulatory and inflammatory macrophages is thought to mainly involve fatty acid oxidation and glycolysis, respectively, which fuel mitochondrial oxidative phosphorylation. However, the association between metabolic pathways and the acquisition of specific macrophage phenotypes remains unclear. This study assessed the relationship between glycolysis and the differentiation of regulatory macrophages. Human monocytes derived from peripheral blood were cultured in vitro in the presence of macrophage colony-stimulating factor to yield regulatory macrophages (M-Mϕs). M-Mϕs had a regulatory macrophage phenotype and produced substantial IL-10 following stimulation with lipopolysaccharide. To analyze the role of glycolysis, glycolysis inhibitors (2-deoxy-d-glucose or dichloroacetate) were added during M-Mϕ differentiation. These cells cultured with glycolysis inhibitors produced significantly lower amounts of IL-10, but produced significantly higher amounts of IL-6 compared to M-Mϕs differentiated without glycolysis inhibitors. Such phenotypic change of M-Mϕs differentiated with glycolysis inhibitors was associated with the alteration of the gene expression pattern related to macrophage differentiation, such as CSF1, MMP9 and VEGFA. M-Mϕs differentiated with glycolysis inhibitors seemed to retain plasticity to become IL-10 producing cells. Furthermore, increased level of pyruvate in culture medium was found to partially reverse the effects of glycolysis inhibitors on cytokine production of M-Mϕs. These results indicate the importance of glycolytic pathway in macrophage differentiation to a regulatory phenotype, and pyruvate may be one of the key metabolites in this process.

Organisms use l-amino acids (l-aa) for most physiological processes. Unlike other organisms, bacteria chiral-convert l-aa to d-configurations as essential components of their cell walls and as signaling molecules in their ecosystems. Mammals recognize microbe-associated molecules to initiate immune responses, but roles of bacterial d-amino acids (d-aa) in mammalian immune systems remain largely unknown. Here, we report that amino acid chirality balanced by bacteria-mammal cross-talk modulates intestinal B cell fate and immunoglobulin A (IgA) production. Bacterial d-aa stimulate M1 macrophages and promote survival of intestinal naïve B cells. Mammalian intestinal d-aa catabolism limits the number of B cells and restricts growth of symbiotic bacteria that activate T cell–dependent IgA class switching of the B cells. Loss of d-aa catabolism results in excessive IgA production and dysbiosis with altered IgA coating on bacteria. Thus, chiral conversion of amino acids is linked to bacterial recognition by mammals to control symbiosis with bacteria.

No abstract

Background/AimsRecent research has highlighted the importance of interactions between commensal fungi and intestinal inflammation. However, there are few studies investigating whether commensal fungi contribute to inflammation in patients with Crohn's disease (CD). The aim of this study is to investigate reveal interactions between commensal fungi and host immune cells in CD.MethodsCD14-positive monocytes were isolated from peripheral blood mononuclear cells from healthy human volunteers and then differentiated in the presence of macrophage colony-stimulating factor (M-CSF) (referred to as M-macrophages, M-Mϕs) or M-CSF and interferon-γ (IFN-γ) (referred to as M-gamma macrophages, Mγ-Mϕs). Cytokine production by these in vitro differentiated macrophages in response to β-(1,3)-glucan was analyzed by flow cytometry. Expression of Dectin-1 was examined using flow cytometry, western blotting, and quantitative reverse transcription-polymerase chain reaction. Cytokine production by in vitro differentiated macrophages in response to β-(1,3)-glucan was measured in the presence of an anti-Dectin-1 receptor antagonist, anti-Syr, or an anti-Fas-1 antibody. Cytokine production by lamina propria mononuclear cells (LPMCs) derived from CD patients in response to β-(1,3)-glucan was also analyzed.ResultsMγ-Mϕs produced a large amount of tumor necrosis factor-α (TNF-α) and interleukin-6 in response to β-(1,3)-glucan. Dectin-1 expression was significantly higher in Mγ-Mϕs than in M-Mϕs. The increase in TNF-α production by Mγ-Mϕs stimulated with glucan was reversed by blocking Dectin-1, Syr or Fas-1. LPMCs derived from CD patients stimulated with β-(1,3)-glucan produced significantly higher amount of TNF-α than LPMCs derived from UC patients.ConclusionsThese results suggest that commensal fungal microbiota may contribute to the pathogenesis of CD by inducing macrophages-derived pro-inflammatory cytokines.