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Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation
Gan Zhao1,2,3, Maria E Gentile4,5,6, Lulu Xue7
1Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. zhaogan@vet.upenn.edu.
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.
Insights
Sparcl1 protein in lung endothelial cells promotes harmful inflammation during infections like influenza and COVID-19. Reducing Sparcl1 may offer a new therapeutic strategy for severe pneumonia.
Area of Science:
- Immunology
- Vascular Biology
- Infectious Disease
Background:
- Lung infection triggers inflammation, impacting both antiviral responses and disease severity.
- The precise mechanisms driving immune pathogenesis and vascular injury in lung infections remain incompletely understood.
Purpose of the Study:
- To investigate the role of Sparcl1, a secreted matricellular protein, in influenza-induced lung injury.
- To explore the potential of Sparcl1 as a biomarker and therapeutic target for pneumonia, including COVID-19.
Main Methods:
- Examined Sparcl1 expression in pulmonary capillary endothelial cells (ECs) during influenza infection.
- Utilized genetic manipulation (overexpression and deletion) of Sparcl1 in vivo and in vitro.
- Investigated the interaction between Sparcl1 and Toll-like receptor 4 (TLR4) signaling in macrophages.
- Assessed Sparcl1 levels in lung ECs and plasma of COVID-19 patients.
Main Results:
- Endothelial Sparcl1 expression is upregulated during influenza-induced lung injury.
- Sparcl1 overexpression exacerbates lung inflammation by promoting M1-like macrophages and pro-inflammatory cytokines.
- Sparcl1 deletion alleviates inflammation; its mechanism involves TLR4 signaling on macrophages.
- Increased Sparcl1 in lung ECs and plasma of COVID-19 patients, with higher levels correlating with fatal outcomes.
Conclusions:
- Endothelial Sparcl1 drives detrimental lung inflammation via TLR4-mediated macrophage activation.
- Sparcl1 serves as a potential prognostic biomarker for severe COVID-19 pneumonia.
- Targeting Sparcl1 presents a promising therapeutic strategy for managing hyperinflammation in pneumonia.
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