Huang Yingqi, Li Rong, Chen Shuo, Wang Qi, Han Zhenyu, Liang Yun, Liang Yao, Li Qianna, Lin Lingming, Wen Qian, Zhou Chaoying, Zhou Xinying, Ma Li
Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, China.
Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Beijing, China.
iScience. 2024 Jun 28;27(8):110238. doi: 10.1016/j.isci.2024.110238. eCollection 2024 Aug 16.
Tuberculosis (TB) is a chronic infectious disease caused by (Mtb) infection, with the highest single-cause mortality. Monocarboxylate transporter 4 (Mct4) transports intracellular lactate outside, but its role in regulating host immune response against Mtb infection remains unknown. Mct4 expression was upregulated in Mtb-infected macrophages and in patients with TB. Mct4 silencing/deficiency significantly decreased Mtb survival in macrophages and in lungs and spleens of mice, while Mct4 overexpression facilitated Mtb survival in macrophages. Furthermore, Mct4 promoted intracellular lactate transport, nuclear factor κB (NF-κB) p65 activation, and interleukin-10 (IL-10) production upon Mtb infection. Mechanistically, IL-10 silencing and IL-10-neutralizing antibody blocked Mct4 overexpressing increased Mtb survival. Replenishing lactate and NF-κB p65 inhibitor JSH23 treatment could inhibit Mct4 overexpressing increased NF-κB p65 activation, IL-10 production, and Mtb survival in macrophages. This study demonstrates that Mct4 promotes Mtb survival through restricting intracellular lactate accumulation to promote NF-κB p65-mediated IL-10 production and suggests Mct4-NF-κB p65-IL-10 axis a potential target for TB treatment.
结核病（TB）是由结核分枝杆菌（Mtb）感染引起的慢性传染病，是单一病因导致死亡率最高的疾病。单羧酸转运蛋白4（Mct4）将细胞内的乳酸转运至细胞外，但其在调节宿主针对Mtb感染的免疫反应中的作用尚不清楚。在Mtb感染的巨噬细胞和结核病患者中，Mct4表达上调。Mct4沉默/缺陷显著降低了巨噬细胞以及小鼠肺和脾中Mtb的存活率，而Mct4过表达则促进了巨噬细胞中Mtb的存活。此外，Mct4在Mtb感染后促进细胞内乳酸转运、核因子κB（NF-κB）p65激活以及白细胞介素-10（IL-10）的产生。机制上，IL-10沉默和IL-10中和抗体阻断了Mct4过表达增加的Mtb存活。补充乳酸和NF-κB p65抑制剂JSH23处理可抑制Mct4过表达增加的NF-κB p65激活、IL-10产生以及巨噬细胞中Mtb的存活。本研究表明，Mct4通过限制细胞内乳酸积累来促进NF-κB p65介导的IL-10产生，从而促进Mtb存活，并提示Mct4-NF-κB p65-IL-10轴是结核病治疗的潜在靶点。
