Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2024 May 18;15(1):4235. doi: 10.1038/s41467-024-48589-3.
Inflammation induced by lung infection is a double-edged sword, moderating both anti-viral and immune pathogenesis effects; the mechanism of the latter is not fully understood. Previous studies suggest the vasculature is involved in tissue injury. Here, we report that expression of Sparcl1, a secreted matricellular protein, is upregulated in pulmonary capillary endothelial cells (EC) during influenza-induced lung injury. Endothelial overexpression of SPARCL1 promotes detrimental lung inflammation, with SPARCL1 inducing 'M1-like' macrophages and related pro-inflammatory cytokines, while SPARCL1 deletion alleviates these effects. Mechanistically, SPARCL1 functions through TLR4 on macrophages in vitro, while TLR4 inhibition in vivo ameliorates excessive inflammation caused by endothelial Sparcl1 overexpression. Finally, SPARCL1 expression is increased in lung ECs from COVID-19 patients when compared with healthy donors, while fatal COVID-19 correlates with higher circulating SPARCL1 protein levels in the plasma. Our results thus implicate SPARCL1 as a potential prognosis biomarker for deadly COVID-19 pneumonia and as a therapeutic target for taming hyperinflammation in pneumonia.
肺部感染引起的炎症是一把双刃剑，调节抗病毒和免疫发病机制的作用; 后者的机制尚未完全了解。先前的研究表明血管参与组织损伤。在这里，我们报告说，在流感诱导的肺损伤期间，分泌细胞外基质蛋白 Sparcl1 在肺毛细血管内皮细胞 (EC) 中上调。内皮细胞中 SPARCL1 的过表达促进有害的肺部炎症，SPARCL1 诱导“M1 样”巨噬细胞和相关的促炎细胞因子，而 SPARCL1 的缺失减轻了这些作用。从机制上讲，SPARCL1 在体外通过巨噬细胞上的 TLR4 发挥作用，而体内 TLR4 抑制可减轻内皮细胞 Sparcl1 过表达引起的过度炎症。最后，与健康供体相比，来自 COVID-19 患者的肺 EC 中 SPARCL1 的表达增加，而致命性 COVID-19 与血浆中循环 SPARCL1 蛋白水平升高相关。因此，我们的研究结果表明 SPARCL1 是致命性 COVID-19 肺炎的潜在预后生物标志物，并可作为控制肺炎过度炎症的治疗靶点。
