Ran Xin, Li Kefei, Li Yutao, Guo Weiwei, Wang Xiaoxuan, Guo Wenjin, Yuan Bao, Liu Juxiong, Fu Shoupeng
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, Jilin, 130062, China.
Department of Laboratory Animals, College of Animal Sciences, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun, Jilin, 130062, China.
Adv Sci (Weinh). 2025 Mar;12(9):e2411947. doi: 10.1002/advs.202411947. Epub 2025 Jan 10.
Staphylococcus aureus (S. aureus) is a major zoonotic pathogen, with mammary gland infections contributing to mastitis, a condition that poses significant health risks to lactating women and adversely affects the dairy industry. Therefore, understanding the immune mechanisms underlying mammary infections caused by S. aureus is essential for developing targeted therapeutic strategies against mastitis. This study identified hydroxycarboxylic acid receptor 2 (HCAR2) as a potential regulator of S. aureus infection in mammary glands. It is demonstrated that HCAR2 deficiency exacerbates the inflammatory response and disrupts the blood-milk barrier in the mammary gland during S. aureus infection, with NLRP3 inflammasome-mediated pyroptosis playing a central role. Activation of HCAR2, on the other hand, suppressed CMPK2 expression, thereby mitigating mitochondrial damage and pyroptosis in mouse mammary epithelial cells (mMECs) induced by S. aureus. Additionally, mitochondrial DNA (mtDNA) released from S. aureus-infected mMECs activates the cGAS/STING signaling pathway in macrophages, impairing their bactericidal activity. In conclusion, this study highlights the critical role of HCAR2 in S. aureus infection of the mammary gland and provides a theoretical basis for identifying potential therapeutic targets for such infections.
金黄色葡萄球菌是一种主要的人畜共患病原体，乳腺感染会导致乳腺炎，这种疾病会给哺乳期妇女带来重大健康风险，并对乳制品行业产生不利影响。因此，了解金黄色葡萄球菌引起的乳腺感染的免疫机制对于制定针对乳腺炎的靶向治疗策略至关重要。本研究确定羟基羧酸受体2（HCAR2）是乳腺中金黄色葡萄球菌感染的潜在调节因子。结果表明，HCAR2缺陷会加剧金黄色葡萄球菌感染期间乳腺的炎症反应并破坏血乳屏障，其中NLRP3炎性小体介导的细胞焦亡起核心作用。另一方面，HCAR2的激活抑制了CMPK2的表达，从而减轻了金黄色葡萄球菌诱导的小鼠乳腺上皮细胞（mMECs）中的线粒体损伤和细胞焦亡。此外，从感染金黄色葡萄球菌的mMECs释放的线粒体DNA（mtDNA）激活巨噬细胞中的cGAS/STING信号通路，损害其杀菌活性。总之，本研究突出了HCAR2在金黄色葡萄球菌乳腺感染中的关键作用，并为确定此类感染的潜在治疗靶点提供了理论依据。
