Macrophage-derived oncostatin M repairs the lung epithelial barrier during inflammatory damage

Tissue repair programs must function alongside antiviral immunity to restore the lung epithelial barrier following infection. We found that macrophage-derived oncostatin M (OSM) counteracted the pathological effects of type I interferon (IFN- I) during infection and damage in mice. At baseline, OSM-deficient mice exhibited altered alveolar type II (ATII) epithelial cell states. In response to influenza or viral mimic challenge, mice lacking OSM exhibited heightened IFN-I responses and increased mortality. OSM delivery to the lung induced ATII proliferation and was sufficient to protect deficient mice against morbidity. Furthermore, OSM promoted organoid formation despite the growth- inhibitory effects of IFN- I. These findings identify OSM as an indispensable macrophage-derived growth factor that maintains the homeostasis of lung epithelial cells and promotes their proliferation to overcome IFN-I–mediated immunopathology. 8-12 week old Osm+/+ and Osm-/- female mice were intranasally with PBS or 225pfu of Influenza A Virus (A/WSN/33; H1N1). Lungs were harvested two days post-infection and digested with Dispase/Liberase/DNase mixture. A portion of the whole lung single cell suspension was stained with TotalSeq-B0301 (Biolegend, Catalog #155831) and TotalSeq-B0302 (Biolegend, Catalog #155833) for hash-tagging before encapsulation.

组织修复程序需与抗病毒免疫协同运作，以在感染后修复肺上皮屏障。本研究发现，在小鼠感染及组织损伤过程中，巨噬细胞来源的抑瘤素M（oncostatin M, OSM）可拮抗I型干扰素（type I interferon, IFN-I）的病理作用。在基础状态下，OSM缺陷小鼠的肺泡II型（alveolar type II, ATII）上皮细胞状态发生改变。经流感病毒或病毒模拟物刺激后，OSM敲除小鼠的IFN-I应答更为强烈，死亡率也有所升高。向肺部递送OSM可诱导ATII细胞增殖，且足以使缺陷小鼠免受疾病困扰。此外，尽管IFN-I具有生长抑制作用，OSM仍可促进类器官（organoid）形成。上述研究结果表明，OSM是一种不可或缺的巨噬细胞源性生长因子，可维持肺上皮细胞稳态并促进其增殖，以抵消IFN-I介导的免疫病理损伤。将8-12周龄的Osm+/+及Osm-/-雌性小鼠经鼻接种磷酸盐缓冲液（phosphate-buffered saline, PBS）或225噬斑形成单位（plaque-forming unit, pfu）的甲型流感病毒（Influenza A Virus, A/WSN/33; H1N1）。于感染后两天采集肺部组织，并用Dispase/Liberase/DNase混合酶液进行消化。取部分全肺单细胞悬液，在封装前用TotalSeq-B0301（Biolegend，货号#155831）及TotalSeq-B0302（Biolegend，货号#155833）进行哈希标记。