Key result
Mast cell deficiency in mice reduces viral myocarditis and fibrosis by limiting Ly6Chigh monocyte influx.
Why the study?
The impact of mast cells on the progression of Coxsackievirus B3-induced viral myocarditis and fibrosis remained to be determined.
Mast cells play a critical role in initiating and modulating the cardiac innate response to CVB3, promoting viral myocarditis and fibrosis via the SCF/MC/CCL2/monocyte/macrophage axis.
Mast cell inhibition merits exploration in viral myocarditis; hypothesis-generating from murine models only.
Mast cells (MCs), central players in allergy and parasitic infections, play key roles in inflammation and fibrosis. Here, the impact of MCs on the progression of Coxsackievirus B3 (CVB3)‐induced viral myocarditis (VMC) and fibrosis was investigated using MC‐deficient KitW‐sh mice. Viral titres, cellular infiltrates and heart pathologies were evaluated and compared with wild‐type (WT) mice during acute CVB3 infection of C57BL/6 mice. CVB3 infection induced an increased accumulation and degranulation of MCs in the hearts of mice during acute infection. MC‐deficient KitW‐sh mice had slightly higher viral titres, decreased VMC and cardiac fibrosis and improved cardiac dysfunction compared to WT mice via decreasing cardiac influx of Ly6Chigh monocytes/macrophages (Mo/Mφ). While bone marrow‐derived MC reconstitution decreased viral titre and worsened improved survival and VMC severity in Wsh mice. MC‐fibroblasts co‐culture revealed a cardiac MC‐fibroblasts crosstalk during early infection: fibroblasts trigger MC degranulation and secretion of CCL2 and tumour necrosis factor alpha (TNF‐α) via producing early stem cell factor (SCF); while MCs‐fibrogenic mediators (TNF‐α) stimulate fibroblasts to increase CCL2, α‐smooth muscle actin (SMA), collagen and transforming growth factor beta（TGFβ) expression, thus aggravating cardiac fibrosis. MCs and fibroblast‐derived CCL2s are both essential for cardiac Ly6Chigh Mo/Mφ influx. Administration of recombinant mouse SCF to CVB3‐infected mice aggravates VMC via accelerating MCs accumulation and cardiac influx of Ly6Chi Mo/Mφ. Collectively, our data highlight an early MC‐fibroblast crosstalk and SCF/MC/CCL2/Mo/Mφ axis as important mechanisms required for triggering VMC and myocardial fibrosis. This finding indicates critical roles of MCs in initiating and modulating cardiac innate response to CVB3 and has an implication in developing new and more effective treatments for VMC.
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Luo et al. (2022) studied Coxsackievirus B3 (CVB3)‐induced viral myocarditis and fibrosis. Mast cell deficiency (KitW-sh mice) vs. Wild-type (WT) mice was evaluated on Viral titres, cellular infiltrates, heart pathologies, cardiac dysfunction, and fibrosis. Mast cell deficiency in mice decreased viral myocarditis severity and cardiac fibrosis, and improved cardiac dysfunction compared to wild-type mice by reducing cardiac influx of Ly6Chigh monocytes.
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