Zhu Liangyu, Cao Wenjing, Li Bingxue, Yang Rui, Wang Yanhong, Wu Hanxin, Peng Li, Huang Xun, Ma Weijie, Zhong Lei, Ma Weijiang, Gao Li, Wu Xinya, Song Jieqin, Yang Jiaru, Luo Suyi, Bao Fukai, Xia Xueshan, Liu Aihua
Yunnan Province Key Laboratory of Children's Major Diseases Research, Department of Pathogen Biology and Immunology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, 650500, China.
Yunnan Province Key Laboratory of Children's Major Diseases Research, Department of Pathogen Biology and Immunology, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, 650500, China; Yunnan Provincial Key Laboratory of Public Health and Biosafety, School of Public Health, Kunming Medical University, Kunming, 650500, China.
Microb Pathog. 2025 Nov;208:107944. doi: 10.1016/j.micpath.2025.107944. Epub 2025 Jul 31.
Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis, survives in host macrophages, the primary effector and antigen-presenting cells involved in the host immune response. We previously showed that Interleukin-32 (IL-32) is significantly increased in the peripheral blood plasma of tuberculosis patients, can act as an anti-MTB agent. However, the underlying molecular mechanism for its effect remains unknown. Here, we showed that inhibiting IL-32 with monoclonal antibody increases MTB loads that was positively correlated with higher antibody concentrations and longer exposure times. RNA-Sequencing result indicated that 3797 genes were shown to be up-regulated in response to IL-32 inhibition, while 1365 genes were down-regulated. GO and KEGG analysis indicated that classical signaling pathways, including TNF, cell cycle, and Wnt were significantly enriched. Consistent expression trends were observed in NF-κB pathway-related antibacterial factors that are functionally capable of inhibiting MTB. Using differentially expressed gene and protein-protein interaction analysis, AEBP1 was the gene with the most significant difference in expression and regulated by IL-32. These findings suggest a dynamic molecular and cellular mechanism by which IL-32 positively regulates the AEBP1-IκBα-NF-κB-TNF-α axis to inhibit MTB infection in human macrophages.
结核分枝杆菌（MTB）是结核病的病原体，可在宿主巨噬细胞中存活，巨噬细胞是参与宿主免疫反应的主要效应细胞和抗原呈递细胞。我们之前发现，白细胞介素-32（IL-32）在结核病患者外周血血浆中显著升高，可作为一种抗MTB药物。然而，其作用的潜在分子机制仍不清楚。在此，我们发现用单克隆抗体抑制IL-32会增加MTB载量，且MTB载量与更高的抗体浓度和更长的暴露时间呈正相关。RNA测序结果表明，3797个基因在IL-32抑制后上调，1365个基因下调。GO和KEGG分析表明，包括TNF、细胞周期和Wnt在内的经典信号通路显著富集。在功能上能够抑制MTB的NF-κB通路相关抗菌因子中观察到一致的表达趋势。通过差异表达基因和蛋白质-蛋白质相互作用分析，AEBP1是表达差异最显著且受IL-32调控的基因。这些发现提示了一种动态分子和细胞机制，即IL-32通过正向调节AEBP1-IκBα-NF-κB-TNF-α轴来抑制人巨噬细胞中的MTB感染。
