α7nAChR on B cells directs T cell differentiation to prevent viral myocarditis
Jing Lu, Keren Chen, Zhihong Cen, Yanlan Huang, Yong Li, LiLi Chen, Weifeng Wu
Jing Lu, Keren Chen, Zhihong Cen, Yanlan Huang, Yong Li, LiLi Chen, Weifeng Wu
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Research Article Cardiology Inflammation

α7nAChR on B cells directs T cell differentiation to prevent viral myocarditis

Abstract

Patients with viral myocarditis (VMC) exhibit evident autonomic nervous system imbalance, and adverse cardiac remodeling is involved in impaired cholinergic function. The α7 nicotinic acetylcholine receptor (α7nAChR), which is a neurotransmitter receptor, exerts immunoregulatory effects. Recent advances have illuminated the evolution and functions of peripheral and cardiac B cells in heart disease. However, the role of α7nAChR expressed by B cells in the progression of VMC has not been established. We revealed the neuroimmune communication landscape in the heart and found that the phenotypes of cardiac and splenic B cells and their α7nAChR expression changed dynamically during the progression of VMC to dilated cardiomyopathy. α7nAChR on B cells serves as a negative regulator by inhibiting their proinflammatory functions and signaling pathways. B cell–specific α7nAChR deficiency exacerbated myocardial inflammation, fibrosis, and cardiac dysfunction. However, these effects were abrogated in non-B cells from mice with IL-17A knockdown. Enhanced degradation of acetylcholine leads to an imbalance in cholinergic signaling, resulting in impaired neurotransmission. The acetylcholinesterase inhibitor pyridostigmine bromide could improve cardiac remodeling and prevent the progression of VMC to the chronic phase, which was partly dependent on the α7nAChR on B cells. Our findings provide notable insights into cardiac-neural-immune communication during myocardial injury.

Authors

Jing Lu, Keren Chen, Zhihong Cen, Yanlan Huang, Yong Li, LiLi Chen, Weifeng Wu

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Figure 6

α7nAChR on B cells restrains their proinflammatory phenotypes, blocking VMC progression in a manner dependent on IL-17A.

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α7nAChR on B cells restrains their proinflammatory phenotypes, blocking ...
(A) Quantification and representative flow histograms of the percentages of MHC-II+, CD40+, CD86+, CD69+, Ki-67+, TNF-α+, and IL-10+ cells among gated CD19+ B cells from recipient spleens are shown (n = 4–9 mice/group). Purified B cells from WT or α7nAChR−/− mice were cultured with or without LPS, anti-CD40, and necrotic cell extract stimulation for 48 hours. (B) Quantification and representative flow histograms of the percentages of MHC-II+, CD40+, CD80+, CD86+, and CD69+ cells among CD19+ B cells cultured in vitro (n = 3–4). (C). Quantitation of in vitro–cultured T cells producing IFN-γ, IL-10, and IL-17 (n = 6). Neutralizing antibodies anti–IL-10 and anti–TNF-α (D) were added to the Transwell coculture system and anti–MHC-II, anti-CD40, anti-CD80, and anti-CD86 (E) were added to the direct coculture system (n = 5); the differentiation of Th cells was observed. The results in B–D were pooled from at least 3 independent experiments. (F) Flowchart showing the experimental scheme for transferring IL-17–/– B cell–depleted splenocytes re-supplemented with purified B cells from WT or α7nAChR−/− mice into SCID mice. (G) Quantification of myocardial pathological score and the percentage of the fibrotic area in IL-17−/− B cell–depleted splenocytes re-supplemented with WT or α7nAChR−/− B lymphocytes on weeks 2 and 5 are shown (n = 6 mice/group). The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) of each group were determined at the endpoint (n = 8–12 mice/group). The data are represented as the mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-tailed, unpaired Student’s t test (A) or 1-way ANOVA (B–D and F).