Immunoglobin attenuates fulminant myocarditis by inhibiting overactivated innate immune response

Abstract

Background and PurposeFulminant myocarditis (FM) is a myocardial inflammatory disease that can result from either viral diseases or autoimmune diseases. In this study, we have determined the treatment effects of immunomodulatory drugs on FM.Experimental ApproachFM was induced in A/JGpt mice by intraperitoneal administration of coxsackievirus B3, after which immunoglobins were administered daily by intraperitoneal injection. On the seventh day, the cardiac structure and function were determined using echocardiography and cardiac catheterisation. Single‐cell RNA sequencing (scRNA‐seq) was performed to evaluate CD45+ cells in the heart.Key ResultsImmunoglobin, a typical immunomodulatory drug, dramatically reduced mortality and significantly improved cardiac function in mice with FM. ScRNA‐seq revealed that immunoglobin treatment effectively modulated cardiac immune homeostasis, particularly by attenuating overactivated innate immune responses. At the cellular level, immunoglobin predominantly targeted Plac8+ monocytes and S100a8+ neutrophils, suppressing their proinflammatory activities, and enhancing antigen processing and presentation capabilities, thereby amplifying the efficiency and potency of the immune response against the virus. Immunoglobin benefits are mediated by the modulation of multiple signalling pathways, including relevant receptors on immune cells, direction of inflammatory cell chemotaxis, antigen presentation and anti‐viral effects. Subsequently, Bst2-ILT7 ligand‐receptor‐mediated cellular interactions manipulated by immunoglobin were further confirmed in vivo.Conclusions and ImplicationsImmunoglobin treatment significantly attenuated FM‐induced cardiac inflammation and improved cardiac function by inhibiting overactivated innate immune responses.