Abstract
Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10–producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.
Highlights
Debilitating autoimmune diseases such as rheumatoid arthritis can arise from the breakdown of immune tolerance
We identified that the mechanisms were conserved between the 2 species and that the conversion of acetate into acetyl-CoA mediated B10 cell differentiation through 2 complementary mechanisms: (a) the increase of energy availability by fueling the TCA cycle and OXPHOS and (b) protein acetylation via ACSS member 2 (ACSS2)
Acetateinduced B10 cells were functional, by alleviating arthritis when adoptively transferred into mice and by inducing Treg differentiation of naive T cells in humans
Summary
Debilitating autoimmune diseases such as rheumatoid arthritis can arise from the breakdown of immune tolerance The cause of such breakdown is not fully known but a key feature is the expansion of proinflammatory Th17 and Th1 T cell subsets, with the concomitant decrease of antiinflammatory Treg subset [1]. A minor subset of B cells, which releases the antiinflammatory cytokine IL-10, plays an important role in immune tolerance. These regulatory B cells, called B10 cells, promote Treg differentiation while inhibiting Th1 and Th17 cells [2]. Patients with rheumatoid arthritis are characterized by a significantly decreased proportion of B10 cells with impaired tolerogenic function [7]. Restoring both the function and the proportion of B10 cells in these patients could serve as a new therapeutic approach that may be applicable to other inflammatory diseases
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