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

Author

Listed:
  • Gan Zhao

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Maria E. Gentile

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Lulu Xue

    (University of Pennsylvania)

  • Christopher V. Cosgriff

    (Massachusetts General Hospital and Harvard Medical School)

  • Aaron I. Weiner

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Stephanie Adams-Tzivelekidis

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Joanna Wong

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Xinyuan Li

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Sara Kass-Gergi

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Nicolas P. Holcomb

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

  • Maria C. Basal

    (University of Pennsylvania
    University of Pennsylvania)

  • Kathleen M. Stewart

    (University of Pennsylvania
    University of Pennsylvania)

  • Joseph D. Planer

    (University of Pennsylvania
    University of Pennsylvania)

  • Edward Cantu

    (University of Pennsylvania
    University of Pennsylvania)

  • Jason D. Christie

    (University of Pennsylvania
    University of Pennsylvania)

  • Maria M. Crespo

    (University of Pennsylvania
    University of Pennsylvania)

  • Michael J. Mitchell

    (University of Pennsylvania)

  • Nuala J. Meyer

    (University of Pennsylvania
    University of Pennsylvania)

  • Andrew E. Vaughan

    (University of Pennsylvania
    University of Pennsylvania
    University of Pennsylvania)

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.

Suggested Citation

  • 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 & K, 2024. "Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48589-3
    DOI: 10.1038/s41467-024-48589-3
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    References listed on IDEAS

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    1. Joey Schyns & Qiang Bai & Cecilia Ruscitti & Coraline Radermecker & Sebastiaan Schepper & Svetoslav Chakarov & Frédéric Farnir & Dimitri Pirottin & Florent Ginhoux & Guy Boeckxstaens & Fabrice Bureau , 2019. "Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    2. Astrid Gillich & Fan Zhang & Colleen G. Farmer & Kyle J. Travaglini & Serena Y. Tan & Mingxia Gu & Bin Zhou & Jeffrey A. Feinstein & Mark A. Krasnow & Ross J. Metzger, 2020. "Capillary cell-type specialization in the alveolus," Nature, Nature, vol. 586(7831), pages 785-789, October.
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