Myocarditis, a severe inflammatory disease, is becoming a worldwide public health concern. This study aims to elucidate the effect of Chemokine (C C motif) receptor-like 2 (CCRL2) in experimental autoimmune myocarditis (EAM) occurrence and its potential regulatory mechanisms.

EAM was simulated in a mouse model injected with α-myosin-heavy chain. The changes on EAM were assessed through histological staining of heart tissues, including measuring cardiac troponin I (cTnI), proinflammatory cytokines, transferase-mediated dUTP nick end labeling (TUNEL) assay, and cardiac function. Then, the heart tissues from the EAM mouse model and control groups were analyzed through transcriptome sequencing to identify the differential expressed genes (DEGs) and hub genes related to pyroptosis. Downregulation of CCRL2 further verified the function of CCRL2 on EAM and p21-activated kinase 1/NOD-like receptor protein 3 (PAK/NLRP3) signaling pathways in vivo.

The EAM model was constructed successfully, with the heart weight/body weight ratio, serum level of cTnI, and concentrations of proinflammatory cytokines elevation. Moreover, cell apoptosis was also significantly increased. Transcriptome sequencing revealed 696 and 120 upregulated and downregulated DEGs, respectively. After functional enrichment, CCRL2 was selected as a potential target. Then, we verified that CCRL2 knockdown improved cardiac function, alleviated EAM occurrence, and reduced PAK/NLRP3 protein expression.

CCRL2 may act as a novel potential treatment target in EAM by regulating the PAK1/NLRP3 pathway.

心肌炎是一种严重的炎症性疾病，正在成为全球公共卫生问题。本研究旨在阐明趋化因子（CC基序）受体样2（CCRL2）在实验性自身免疫性心肌炎（EAM）发生中的作用及其潜在的调节机制。

在注射 α-肌球蛋白重链的小鼠模型中模拟 EAM。通过心脏组织的组织学染色评估 EAM 的变化，包括测量心肌肌钙蛋白 I (cTnI)、促炎细胞因子、转移酶介导的 dUTP 缺口末端标记 (TUNEL) 测定和心功能。然后，通过转录组测序对 EAM 小鼠模型和对照组的心脏组织进行分析，以确定与细胞焦亡相关的差异表达基因（DEG）和枢纽基因。 CCRL2 的下调进一步验证了 CCRL2 在体内对 EAM 和 p21 激活激酶 1/NOD 样受体蛋白 3 (PAK/NLRP3) 信号通路的功能。

EAM模型构建成功，心脏重量/体重比、血清cTnI水平、促炎细胞因子浓度升高。此外，细胞凋亡也显着增加。转录组测序显示分别有 696 个和 120 个上调和下调的 DEG。经过功能富集后，CCRL2被选为潜在靶点。然后，我们验证了 CCRL2 敲低可改善心脏功能、减轻 EAM 发生并减少 PAK/NLRP3 蛋白表达。

CCRL2 可能通过调节 PAK1/NLRP3 通路作为 EAM 的新型潜在治疗靶点。