LncRNA MAAMT facilitates macrophage recruitment and proinflammatory activation and exacerbates autoimmune myocarditis through the SRSF1/NF-κB axis

Abstract

Long non-coding RNAs (lncRNAs) have been implicated in dilated cardiomyopathy (DCM). However, the biological functions and regulatory mechanisms underlying DCM remain elusive. Using a mouse model of experimental autoimmune myocarditis (EAM) to mimic DCM, we successfully constructed a dynamic lncRNA expression library for EAM by lncRNA microarray and found that the expression of a macrophage-enriched lncRNA, MAAMT, was significantly increased in the myocardial tissue of mice at the acute stage of EAM. Functionally, MAAMT knockdown alleviated the recruitment and proinflammatory activation of macrophages of heart, spleen, and peripheral blood of mice at the acute stage of EAM, reduced myocardial inflammation and injury, and eventually reversed ventricular remodelling and improved cardiac function in chronic EAM model mice. Mechanistically, we identified serine/arginine-rich splicing factor 1 (SRSF1) as an MAAMT-interacting protein in macrophages using RNA pull-down assays coupled with mass spectrometry. MAAMT knockdown attenuated the ubiquitination-mediated degradation of SRSF1, increased the protein expression of SRSF1, and restrained the activation of the NF-κB pathway in macrophages, thereby inhibiting the proinflammatory activation of macrophages. Collectively, our results demonstrate that MAAMT is a key proinflammatory regulator of myocarditis that promotes macrophage activation through the SRSF1-NF-κB axis, providing a new insight into early effective treatment strategies for DCM.