Elsevier

Journal of Hepatology

Volume 79, Issue 2, August 2023, Pages 296-313
Journal of Hepatology

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

https://doi.org/10.1016/j.jhep.2023.04.037Get rights and content
Under a Creative Commons license
open access

Highlights

  • Intestinal B cells are metabolically activated in NASH mouse models, and increased in murine and human NASH.

  • NASH intestinal B cells are activated independently of the gut microbiota.

  • B cells promote metabolic T-cell activation in the gastrointestinal tract independently of TCR signalling.

  • IgA secretion and FcRγ signalling on MoMFs/SAMacs aggravate hepatic fibrosis in mice and patients with NASH.

  • Genetic and therapeutic B-cell abrogation reduced T-cell-driven inflammation and fibrosis in NASH.

Background & Aims

The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.

Methods

C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans.

Results

Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis.

Conclusions

Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH.

Impact and Implications

There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis.

Keywords

NAFLD
NAFL
NASH
HCC
fibrosis
B cells
gut-liver axis

Cited by (0)

Author names in bold designate shared co-first authorship

§

Current address: Roche Pharmaceutical Research and Early Development Oncology, Roche Innovation Center Munich, Penzberg, Germany

These authors contributed equally: Elena Kotsiliti & Valentina Leone

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These authors contributed equally: Svenja Schuehle & Olivier Govaere