Yahui Song

Myocarditis is a potentially fatal disease that can progress to inflammatory dilated cardiomyopathy (DCMi), a condition that is a leading cause of noncongenital heart failure in young adults. However, the mechanisms driving the transition from acute myocarditis to DCMi remain poorly understood. Although IL-17A-mediated inflammation is a well-known driver of this progression, the intracellular regulators that sustain and amplify this response remain unclear. Here, we identify the E3 ubiquitin ligase TRIM21, which is upregulated in the hearts of DCMi patients and experimental autoimmune myocarditis (EAM) mice, as a key amplifier of IL-17A-driven inflammation in cardiac fibroblasts (CFs), promoting disease progression and fibrosis. TRIM21 deficiency significantly attenuates EAM progression, reducing inflammatory cell infiltration and fibrotic remodeling. Mechanistically, TRIM21 is induced by IL-17A in CFs and promotes K27-linked polyubiquitination and lysosomal degradation of TRAF3, a negative regulator of IL-17A signaling, thereby establishing a self-reinforcing IL-17A-TRIM21–TRAF3 positive feedback loop. Finally, specific knockdown of TRIM21 in CFs via the AAV9-Postn strategy effectively alleviates EAM severity. These findings identify TRIM21 as an intracellular mediator of sustained IL-17A signaling in myocarditis and highlight its potential as a therapeutic target for preventing progression to DCMi.

The stimulator of interferon genes (STING) serves as a pivotal signaling hub in innate immunity, orchestrating type I interferon (IFN-I) and pro-inflammatory responses upon detection of cytosolic DNA. While the canonical cyclic GMP-AMP synthase (cGAS)-STING axis has been extensively studied in host defense and sterile inflammation, increasing evidence indicates that STING can also be activated through a variety of both pattern recognition receptors (PRRs)-dependent and PRRs-independent mechanisms. In this review, we comprehensively summarize the molecular pathways through which PRRs—including cGAS, interferon gamma inducible protein 16 (IFI16), DEAD-box helicase 41 (DDX41), and DNA-dependent protein kinase (DNA-PK)—engage and regulate STING activation. Beyond PRRs-triggered pathways, we explore emerging evidence of PRRs-independent STING activation, driven by genetic mutations, endoplasmic reticulum (ER) stress, dysregulated intracellular trafficking, and impaired protein degradation. These mechanisms contribute to the pathogenesis of a broad spectrum of inflammatory and autoimmune disorders affecting multiple organ systems, including the digestive, cardiovascular, renal, pulmonary, and nervous systems. We also highlight the current landscape of pharmacological inhibitors targeting cGAS and STING, categorized according to their mechanisms of action and therapeutic potential. The redundancy and complexity of components within the STING signaling network present challenges in effectively suppressing inflammatory overactivation by targeting a single molecule. Nevertheless, the central role of STING offers multiple opportunities for therapeutic intervention, whether by modulating upstream or downstream signaling elements. This review not only provides a systematic framework for understanding the intricacies of STING signaling, but offers insights into the development of next-generation therapeutics aimed at selectively modulating STING activity in disease contexts.

Inflammasomes are cytosolic sensors of pathogens. Their activation can lead to the induction of caspase-1-mediated inflammatory responses and the release of several proinflammatory cytokines, including IL-1β. There is a complex relationship between viral infection and the nucleotide-binding oligomerization domain-like receptors family pyrin domain-containing 3 (NLRP3) inflammasome. The activation of the NLRP3 inflammasome is essential for antiviral immunity, while excessive NLRP3 inflammasome activation may lead to excessive inflammation and pathological damage. Meanwhile, viruses have evolved strategies to suppress the activation of inflammasome signaling pathways, thus escaping immune responses. In this study, we investigated the inhibitory effect of coxsackievirus B3 (CVB3), a positive single-strand RNA virus, on the activation of the NLRP3 inflammasome in macrophages. CVB3-infected mice had significantly lower production of IL-1β and a lower level of NLRP3 in the small intestine after LPS stimulation. Furthermore, we found that CVB3 infection inhibited NLRP3 inflammasome activation and IL-1β production in macrophages by suppressing the NF-κB signaling pathway and ROS production. Additionally, CVB3 infection increased the susceptibility of mice to Escherichia coli infection by decreasing IL-1β production. Collectively, our study revealed a novel mechanism of NLRP3 inflammasome activation by suppressing the NF-κB pathway and ROS production in LPS-induced macrophages. Our findings may provide new ideas for antiviral treatment and drug development for CVB3 infection.