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Gastrointestinal B-cells license metabolic T-cell activation in NASH microbiota anigen-independently and contribute to fibrosis by IgA-FcRy signalling

ABSTRACT: Non-alcoholic steatohepatitis (NASH) is a T-cell mediated, auto-aggressive condition that can result in progressive liver disease and hepatocellular carcinoma. Gastrointestinal B-cells are activated and increased in number in mouse and human NASH, licensing metabolic-cell activation to induce NASH antigen- and microbiota-independently. Genetic or therapeutic depletion of B-cells systemically or gastrointestinal B-cells specifically prevented or reverted NASH and fibrosis. Clinical and molecular analyses from NASH patients demonstrated IgA-levels and activated FcRy+ hepatic myeloid cells to correlate with liver fibrosis degree.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190487 | GEO | 2022/02/01

REPOSITORIES: GEO

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Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

Project description:Non-alcoholic steatohepatitis (NASH), which is increasing in incidence due to the obesity epidemic, is a T-cell mediated, auto-aggressive condition that can result in progressive liver disease and hepatocellular carcinoma (HCC). The gut-liver axis contributes to NASH, yet mechanisms underlying metabolic T-cell activation and NASH-related fibrosis have largely remained elusive. We found that gastrointestinal B-cells are activated and increased in number in mouse/human NASH, allowing metabolic T-cell activation to induce NASH antigen- and microbiota-independently. Genetic/therapeutic depletion of B-cells systemically or of gastrointestinal B-cells specifically, prevented or reverted NASH and fibrosis. Secretion of immunoglobulins was essential for NASH and fibrosis development. IgA secretion was necessary for fibrosis-induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcRγ signaling-axis. Furthermore, clinical/molecular analyses from NASH-patients demonstrated IgA and activated FcRγ+ hepatic myeloid cells to correlate with the degree of liver-fibrosis. Thus, gastrointestinal B-cells and the IgA-FcRγ signaling-axis on hepatic myeloid cells represent potential therapeutic targets to treat NASH.

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Gastrointestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcRγ signaling

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Gastrointestinal B-cells license metabolic T-cell activation in NASH microbiota anigen-independently and contribute to fibrosis by IgA-FcRy signalling

Project description:Gastrointestinal B-cells license metabolic T-cell activation in NASH microbiota anigen-independently and contribute to fibrosis by IgA-FcRy signalling

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Project description:Non-alcoholic fatty liver disease is continuum of disorders among which non-alcoholic steatohepatitis (NASH) is particularly associated with a negative prognosis. Hepatocyte lipotoxicity is one of the main pathogenic factors of liver fibrosis and NASH. However, the molecular mechanisms regulating this process are poorly understood. Here, we integrated transcriptomic and chromatin accessibility analyses from human liver and mouse hepatocytes to identify lipotoxicity-sensitive transcription factors. We found that several transcription factors that were activated in liver from NASH patients and by mouse hepatocyte lipotoxicity. Notably, the gene expression linked to lipotoxicity closely correlated with transcriptional patters in fibrosis progression in NASH patients. Collectively, our findings uncovered novel molecular insights into lipotoxicity-induced NASH.

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