Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation

Gan Zhao (), Maria E. Gentile, Lulu Xue, Christopher V. Cosgriff, Aaron I. Weiner, Stephanie Adams-Tzivelekidis, Joanna Wong, Xinyuan Li, Sara Kass-Gergi, Nicolas P. Holcomb, Maria C. Basal, Kathleen M. Stewart, Joseph D. Planer, Edward Cantu, Jason D. Christie, Maria M. Crespo, Michael J. Mitchell, Nuala J. Meyer and Andrew E. Vaughan ()
Additional contact information
Gan Zhao: University of Pennsylvania
Maria E. Gentile: University of Pennsylvania
Lulu Xue: University of Pennsylvania
Christopher V. Cosgriff: Massachusetts General Hospital and Harvard Medical School
Aaron I. Weiner: University of Pennsylvania
Stephanie Adams-Tzivelekidis: University of Pennsylvania
Joanna Wong: University of Pennsylvania
Xinyuan Li: University of Pennsylvania
Sara Kass-Gergi: University of Pennsylvania
Nicolas P. Holcomb: University of Pennsylvania
Maria C. Basal: University of Pennsylvania
Kathleen M. Stewart: University of Pennsylvania
Joseph D. Planer: University of Pennsylvania
Edward Cantu: University of Pennsylvania
Jason D. Christie: University of Pennsylvania
Maria M. Crespo: University of Pennsylvania
Michael J. Mitchell: University of Pennsylvania
Nuala J. Meyer: University of Pennsylvania
Andrew E. Vaughan: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48589-3

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