1. Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation.
- Author
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Zhao G, Gentile ME, Xue L, Cosgriff CV, Weiner AI, Adams-Tzivelekidis S, Wong J, Li X, Kass-Gergi S, Holcomb NP, Basal MC, Stewart KM, Planer JD, Cantu E, Christie JD, Crespo MM, Mitchell MJ, Meyer NJ, and Vaughan AE
- Subjects
- Animals, Humans, Mice, Toll-Like Receptor 4 metabolism, Toll-Like Receptor 4 genetics, Calcium-Binding Proteins metabolism, Calcium-Binding Proteins genetics, Mice, Inbred C57BL, Pneumonia, Viral immunology, Pneumonia, Viral pathology, Pneumonia, Viral virology, Pneumonia, Viral metabolism, Male, Macrophages metabolism, Macrophages immunology, Female, Mice, Knockout, Extracellular Matrix Proteins, COVID-19 immunology, COVID-19 virology, COVID-19 metabolism, COVID-19 pathology, Endothelial Cells metabolism, Endothelial Cells virology, Endothelial Cells immunology, Macrophage Activation, SARS-CoV-2 physiology, Lung virology, Lung pathology, Lung immunology
- Abstract
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., (© 2024. The Author(s).)
- Published
- 2024
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