Krebs Adam, Lazarov Tomi, Reynolds Anthony, Dill-McFarland Kimberly A, Xie Abigail, Bean James, Du Muxue, Levy Olivier, Buglino John, Zhong Aaron, Neehus Anna-Lena, Boisson-Dupuis Stephanie, Casanova Jean-Laurent, Kroon Elouise E, Möller Marlo, Hawn Thomas R, Zhou Ting, Finley Lydia W S, Juste Marc Antoine Jean, Fitzgerald Dan, Geissmann Frederic, Glickman Michael S
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine, New York, NY, USA.
bioRxiv. 2025 Jul 26:2025.07.23.664455. doi: 10.1101/2025.07.23.664455.
(Mtb) must survive within multiple macrophage populations during infection, including alveolar macrophages (AM) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1 mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to (Mtb) infection. The role of itaconate in human macrophages is less clear and whether itaconate mediates distinct effects in macrophage subtypes is unknown. Here, we investigated the role of itaconate in human iPSC-derived macrophages, either induced by GM-CSF to resemble alveolar macrophages (AM-Like cells), or treated with M-CSF to generate control macrophages (MCDM cells). Both types of human macrophages produce substantially less itaconate than mouse macrophages and AM-Ls produced 4-fold less itaconate than MCDMs. Surprisingly, ACOD1 deficient AM-L macrophages, but not MCDM macrophages, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb induced inflammatory response in MCDMs, but not AM-L macrophages, affecting both the Type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to TB, with distinct roles in different macrophage subsets. These results also show that genetically tractable hiPSC-derived macrophages are a robust and versatile model to dissect cellular host pathogen interactions.
结核分枝杆菌（Mtb）在感染过程中必须在多种巨噬细胞群体中存活，包括肺泡巨噬细胞（AM）和募集的炎性巨噬细胞。在小鼠中，巨噬细胞通过ACOD1介导乌头酸脱羧产生的衣康酸具有直接抗菌活性，可调节炎性细胞因子，并且是抵抗Mtb感染所必需的。衣康酸在人类巨噬细胞中的作用尚不清楚，并且衣康酸是否在巨噬细胞亚型中介导不同的作用也未知。在这里，我们研究了衣康酸在人诱导多能干细胞衍生的巨噬细胞中的作用，这些巨噬细胞要么由GM-CSF诱导以类似于肺泡巨噬细胞（AM样细胞），要么用M-CSF处理以产生对照巨噬细胞（MCDM细胞）。这两种类型的人类巨噬细胞产生的衣康酸都比小鼠巨噬细胞少得多，并且AM-L产生的衣康酸比MCDM少4倍。令人惊讶的是，ACOD1缺陷的AM-L巨噬细胞而非MCDM巨噬细胞允许Mtb生长。此外，衣康酸起到抑制Mtb诱导的MCDM炎性反应的作用，但对AM-L巨噬细胞不起作用，影响I型干扰素和TNF途径。这些结果表明衣康酸参与人类巨噬细胞对结核病的反应，在不同的巨噬细胞亚群中具有不同的作用。这些结果还表明，具有遗传易处理性的人诱导多能干细胞衍生的巨噬细胞是剖析细胞宿主病原体相互作用的强大且通用的模型。
