Kajiwara Chiaki, Shiozawa Ayako, Urabe Naohisa, Yamaguchi Tetsuo, Kimura Soichiro, Akasaka Yoshikiyo, Ishii Yoshikazu, Tateda Kazuhiro
Department of Microbiology and Infectious Diseases, Faculty of Medicine, Toho University School of Medicine, Tokyo, Japan.
Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan.
J Immunol. 2023 Feb 15;210(4):431-441. doi: 10.4049/jimmunol.2200306.
In Mycobacterium avium infections, macrophages play a critical role in the host defense response. Apoptosis inhibitor of macrophage (AIM), also known as CD5L, may represent a novel supportive therapy against various diseases, including metabolic syndrome and infectious diseases. The mechanisms of AIM include modulating lipid metabolism in macrophages and other host cells. We investigated the role of AIM in M. avium infections in vitro and in vivo. In a mouse model of M. avium pneumonia, foamy macrophages were induced 6 wk after infection. The bacteria localized in these macrophages. Flow cytometric analysis also confirmed that the percentage of CD11chighMHCclassIIhigh interstitial and alveolar macrophages, a cell surface marker defined as foamy macrophages, increased significantly after infection. AIM in alveolar lavage fluid and serum gradually increased after infection. Administration of recombinant AIM significantly increased the number of bacteria in the lungs of mice, accompanied by the induction of inflammatory cytokine and iNOS expression. In mouse bone marrow-derived macrophages, the mRNA expression of AIM after M. avium infection and the amount of AIM in the supernatant increased prior to the increase in intracellular bacteria. Infected cells treated with anti-AIM Abs had fewer bacteria and a higher percentage of apoptosis-positive cells than infected cells treated with isotype control Abs. Finally, AIM in the sera of patients with M. avium-pulmonary disease was measured and was significantly higher than in healthy volunteers. This suggests that AIM production is enhanced in M. avium-infected macrophages, increasing macrophage resistance to apoptosis and providing a possible site for bacterial growth.
在鸟分枝杆菌感染中，巨噬细胞在宿主防御反应中起关键作用。巨噬细胞凋亡抑制因子（AIM），也称为CD5L，可能代表一种针对包括代谢综合征和传染病在内的各种疾病的新型支持性疗法。AIM的机制包括调节巨噬细胞和其他宿主细胞中的脂质代谢。我们在体外和体内研究了AIM在鸟分枝杆菌感染中的作用。在鸟分枝杆菌肺炎小鼠模型中，感染6周后诱导出泡沫状巨噬细胞。细菌定位于这些巨噬细胞中。流式细胞术分析还证实，感染后，作为泡沫状巨噬细胞定义的细胞表面标志物CD11chighMHCII类高间质和肺泡巨噬细胞的百分比显著增加。感染后肺泡灌洗液和血清中的AIM逐渐增加。给予重组AIM显著增加了小鼠肺内的细菌数量，并伴有炎性细胞因子和诱导型一氧化氮合酶表达的诱导。在小鼠骨髓来源的巨噬细胞中，鸟分枝杆菌感染后AIM的mRNA表达和上清液中AIM的量在细胞内细菌增加之前就增加了。用抗AIM抗体处理的感染细胞比用同型对照抗体处理的感染细胞细菌更少，凋亡阳性细胞百分比更高。最后，测量了鸟分枝杆菌肺病患者血清中的AIM，其显著高于健康志愿者。这表明在鸟分枝杆菌感染的巨噬细胞中AIM产生增加，增加了巨噬细胞对凋亡的抗性，并为细菌生长提供了一个可能的场所。
