Targeting Mcl-1 to Restore IL-10-Driven Breg Suppression Reverses Allergic Asthma.

Authors

Le Liu, Lihua Mo, Yan Feng, Hui Huangfu, Pingchang Yang, Chenyang Li, Xiaoyu Liu

Published in

Immunology letters. Pages 107244. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Regulatory B cells (Bregs) suppress allergic inflammation primarily through interleukin-10 (IL-10), yet the intrinsic mechanisms constraining their regulatory capacity remain incompletely understood. Although the anti-apoptotic protein Mcl-1 is essential for B cell survival, its potential non-canonical roles in Breg-mediated immune regulation are unknown.
B cell-specific Mcl1^ΔCD19mice and OVA-induced airway allergy models were used to assess Breg function. Translational studies employed lentiviral MCL1overexpression in primary human B cells, PBMC-reconstituted NSG mice, and clinical B cell profiling from asthma patients. Rigorous experimental controls were implemented to exclude confounding effects from B cell developmental defects and compensatory anti-apoptotic signaling.
Compared with littermate controls, Mcl1^ΔCD19mice exhibited significantly attenuated airway hyperresponsiveness, pulmonary eosinophilia, and antigen-specific IgE levels (all p< 0.01), accompanied by a 4.2-fold increase in the absolute number of IL-10⁺Bregs (p< 0.001). B cells isolated from Mcl1^ΔCD19mice potently suppressed Th2 cytokine production and promoted type 1 regulatory T (Tr1) cell differentiation in an IL-10R-dependent manner. Mechanistically, Mcl-1 associates with the Il10promoter; this chromatin binding coincides with enrichment of the repressive histone mark H3K27me3 and reduced recruitment of RNA polymerase II. In humanized mice, enforced MCL1 overexpression in human B cells reduced IL-10 secretion by 65% and exacerbated airway inflammation. Furthermore, B cells from asthma patients displayed elevated endogenous MCL1 expression and correspondingly diminished IL-10 production. It should be noted that our human-subject analysis is limited by modest sample size, and further validation in larger patient cohorts is required.
Mcl-1 functions as an epigenetic suppressor of Il10transcription in B cells, independently of its canonical pro-survival role, thereby restraining Breg-mediated immune tolerance and promoting allergic airway inflammation. The B-cell Mcl-1/IL-10 axisrepresents a promising preclinical pathway for further investigation as a potential therapeutic target for allergic asthma, though pharmacological validation is still needed.

PMID:
42810527
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

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