Alveolar macrophages (AMs) are the major lung-resident macrophages and have contradictory functions. AMs maintain tolerance and tissue homeostasis, but they also initiate strong inflammatory responses. However, such opposing roles within the AM population were not known to be simultaneously generated and coexist. Here, we uncovered heterogeneous AM subpopulations generated in response to two distinct pulmonary fungal infections, Cryptococcus neoformans and Aspergillus fumigatus. Some AMs are bona fide sentinel cells that produce chemoattractant CXCL2, which also serves as a marker for AM heterogeneity, in the context of pulmonary fungal infections. However, other AMs do not produce CXCL2 and other pro-inflammatory molecules. Instead, they highly produce anti-inflammatory molecules, including interleukin-10 (IL-10) and complement component 1q (C1q). These two AM subpopulations have distinct metabolic profiles and phagocytic capacities. We report that polarization of pro-inflammatory and anti-inflammatory AM subpopulations is regulated at both epigenetic and transcriptional levels and that these AM subpopulations are generally highly plastic. Our studies have uncovered the role of C1q expression in programming and sustaining anti-inflammatory AMs. Our finding of the AM heterogeneity upon fungal infections suggests a possible pharmacological intervention target to treat fungal infections by tipping the balance of AM subpopulations.

肺泡巨噬细胞 (AMs) 是主要的肺驻留巨噬细胞，具有相互矛盾的功能。AM 维持耐受性和组织稳态，但它们也会引发强烈的炎症反应。然而，并不知道 AM 群体中的这种对立角色是同时产生和共存的。在这里，我们发现了为响应两种不同的肺部真菌感染，新型隐球菌和烟曲霉而产生的异质 AM 亚群. 一些 AM 是真正的前哨细胞，可产生化学引诱物 CXCL2，在肺部真菌感染的情况下，CXCL2 也可作为 AM 异质性的标志物。然而，其他 AM 不产生 CXCL2 和其他促炎分子。相反，它们会大量产生抗炎分子，包括白细胞介素 10 (IL-10) 和补体成分 1q (C1q)。这两个 AM 亚群具有不同的代谢特征和吞噬能力。我们报告说，促炎和抗炎 AM 亚群的极化在表观遗传和转录水平上均受到调节，并且这些 AM 亚群通常具有高度可塑性。我们的研究揭示了 C1q 表达在编程和维持抗炎 AMs 中的作用。