TRIM21 Enhances IL-17A Signaling and Drives Autoimmune Myocarditis by Promoting TRAF3 Lysosomal Degradation in Cardiac Fibroblasts
Myocarditis is a major health concern worldwide, often progressing to dilated cardiomyopathy (DCM) and sudden death, particularly in young individuals. However, the mechanisms driving the transition from acute myocarditis to inflammatory DCM (DCMi) remain unclear. Autoimmune responses, especially those involving interleukin (IL)-17A signaling, have been implicated, though the specific cellular targets and upstream regulators in the cardiac environment are not well understood. Here, we identify TRIM21, an E3 ubiquitin ligase, as a key regulator in this process. Using the experimental autoimmune myocarditis (EAM) model, we show that TRIM21 expression is significantly upregulated in cardiac fibroblasts (CFs) during DCMi and upon IL-17A stimulation. Surprisingly, TRIM21 deficiency attenuated EAM progression, reducing inflammatory neutrophils and Ly6Chigh monocytes/macrophages infiltration. Bone marrow chimeric and IL-17A neutralization experiments confirmed TRIM21's role in CFs, where it promotes IL-17A signaling by facilitating TRAF3 degradation via K27-linked polyubiquitination. These findings identify TRIM21 as a new target in CFs and uncover a regulatory mechanism for IL-17A signaling, suggesting that therapies targeting TRIM21 may need to be adapted to different microenvironments. Overall design: To investigate the regulatory mechanism of E3 ubiquitin ligase TRIM21 in autoimmune myocarditis, we constructed an autoimmune myocarditis model using BALB/C and TRIM21 knockout mice. Subsequently, we performed RNA sequencing on the hearts of control mice on day 0 and BALB/C and TRIM21 knockout mice subjected to experimental autoimmune myocarditis (EAM) for 21 days. Finally, we conducted gene expression profile analysis using the RNA-seq data obtained.