1,25-dihydroxyvitamin D deficiency accelerates inflammatory response by up-regulating inositol 1,4,5-triphosphate receptor in Coxsackievirus B3-induced acute myocarditis

Acute myocarditis (AM) is an inflammatory disease of the myocardium primarily induced by pathogen infection. The exacerbated inflammatory response, which is one of the main drivers of rapid deterioration and mortality in AM, has become a focal point of research. Numerous studies have demonstrated that vitamin D deficiency serves as a significant risk factor for disease progression in various conditions, including infections and cardiovascular disorders, which has garnered substantial attention in recent years. However, the specific impact of vitamin D deficiency on inflammatory responses in AM remains poorly understood and requires further investigation. Here, we demonstrate that AM patients with vitamin D deficiency exhibit heightened inflammatory responses, and that vitamin D levels are negatively correlated with serum pro-inflammatory factors (IL-1β, IL-6, IFN-γ and TNF-α). Furthermore, In the Coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC) murine model, we further demonstrated that targeted knockout of the 1α(OH)ase gene, which induces 1,25-dihydroxyvitamin D3 [1,25(OH)₂D₃] deficiency, exacerbated AVMC symptom severity and potentiated inflammatory responses. Importantly, we identified cellular senescence, rather than viral replication capacity, as the key factor through which 1,25(OH)₂D₃ deficiency influences AVMC inflammatory responses. Notably, we found that exogenous supplementation of 1,25(OH)₂D₃ ameliorates cardiomyocyte senescence and reduces AVMC inflammatory responses. Mechanistically, 1,25(OH)₂D₃ modulates AVMC inflammatory responses through the negative regulation of IP3R2-mediated cellular senescence. In conclusion, our research shows that 1,25(OH)₂D₃ deficiency is a key risk factor for AVMC inflammation and highlights IP3R2 as a novel mediator in the vitamin D-senescence-inflammation axis, marking it as a potential therapeutic target.