Tissue-resident macrophages are a diverse population of cells that perform specialized functions including sustaining tissue homeostasis and tissue surveillance. Here, we report an interstitial subset of CD169⁺ lung-resident macrophages that are transcriptionally and developmentally distinct from alveolar macrophages (AMs). They are primarily localized around the airways and are found in close proximity to the sympathetic nerves in the bronchovascular bundle. These nerve- and airway-associated macrophages (NAMs) are tissue resident, yolk sac derived, self-renewing, and do not require CCR2⁺ monocytes for development or maintenance. Unlike AMs, the development of NAMs requires CSF1 but not GM-CSF. Bulk population and single-cell transcriptome analysis indicated that NAMs are distinct from other lung-resident macrophage subsets and highly express immunoregulatory genes under steady-state and inflammatory conditions. NAMs proliferated robustly after influenza infection and activation with the TLR3 ligand poly(I:C), and in their absence, the inflammatory response was augmented, resulting in excessive production of inflammatory cytokines and innate immune cell infiltration. Overall, our study provides insights into a distinct subset of airway-associated pulmonary macrophages that function to maintain immune and tissue homeostasis.

组织驻留巨噬细胞是一个多样化的细胞群，它们执行特殊功能，包括维持组织稳态和组织监测。在这里，我们报告了 CD169 ⁺肺驻留巨噬细胞的间质子集，它们在转录和发育上与肺泡巨噬细胞 (AMs) 不同。它们主要位于气道周围，靠近支气管血管束的交感神经。这些神经和气道相关巨噬细胞 (NAM) 是组织驻留、卵黄囊衍生、自我更新的，不需要 CCR2 ⁺用于发育或维持的单核细胞。与 AM 不同，NAM 的开发需要 CSF1 而不是 GM-CSF。群体和单细胞转录组分析表明，NAMs 与其他肺内巨噬细胞亚群不同，并且在稳态和炎症条件下高度表达免疫调节基因。NAMs 在流感感染和 TLR3 配体 poly(I:C) 激活后迅速增殖，在它们缺失的情况下，炎症反应增强，导致炎症细胞因子的过度产生和先天免疫细胞浸润。总体而言，我们的研究提供了对气道相关肺巨噬细胞的独特亚群的见解，这些巨噬细胞具有维持免疫和组织稳态的功能。