Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation
Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation
Abstract Inflammation upon infectious lung injury is a double-edged sword: while tissue-infiltrating immune cells and cytokines are necessary to control infection, these same factors often aggravate injury. Full appreciation of both the sources and targets of inflammatory mediators is required to facilitate strategies to maintain antimicrobial effects while minimizing off-target epithelial and endothelial damage. Recognizing that the vasculature is centrally involved in tissue responses to injury and infection, we observed that pulmonary capillary endothelial cells (ECs) exhibit dramatic transcriptomic changes upon influenza injury punctuated by profound upregulation of Sparcl1. Endothelial deletion and overexpression of SPARCL1 implicated this secreted matricellular protein in driving key pathophysiologic symptoms of pneumonia, which we demonstrate result from its effects on macrophage polarization. SPARCL1 induces a shift to a pro-inflammatory “M1-like” phenotype (CD86+CD206-), thereby increasing associated cytokine levels. Mechanistically, SPARCL1 acts directly on macrophages in vitro to induce the pro-inflammatory phenotype via activation of TLR4, and TLR4 inhibition in vivo ameliorates inflammatory exacerbations caused by endothelial Sparcl1 overexpression. Finally, we confirmed significant elevation of SPARCL1 in COVID-19 lung ECs in comparison with those from healthy donors. Survival analysis demonstrated that patients with fatal COVID-19 had higher levels of circulating SPARCL1 protein compared to those who recovered, indicating the potential of SPARCL1 as a biomarker for prognosis of pneumonia and suggesting that personalized medicine approaches might be harnessed to block SPARCL1 and improve outcomes in high-expressing patients.
Stewart Kathleen M.、Zhao Gan、Adams-Tzivelekidis Stephanie、Li Xinyuan、Kass-Gergi Sara、Crespo Maria M.、Meyer Nuala J.、Mitchell Michael J.、Basal Maria C.、Wong Joanna、Cosgriff Christopher V.、Planer Joseph D.、Weiner Aaron I.、Gentile Maria E.、Xue Lulu、Vaughan Andrew E.、Cantu Edward、Holcomb Nicolas P.、Christie Jason D.
Penn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaInstitute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of PennsylvaniaPenn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of PennsylvaniaPenn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaPenn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaMassachusetts General Hospital and Harvard Medical SchoolPenn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaDepartment of Bioengineering, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaPenn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Cardiovascular Surgery, Department of Surgery, Perelman School of Medicine, University of PennsylvaniaDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania||Institute for Regenerative Medicine, University of Pennsylvania||Penn-CHOP Lung Biology Institute, University of PennsylvaniaPenn-CHOP Lung Biology Institute, University of Pennsylvania||Division of Pulmonary Department of Medicine, Perelman School of Medicine, University of Pennsylvania
基础医学生物科学研究方法、生物科学研究技术生理学
Stewart Kathleen M.,Zhao Gan,Adams-Tzivelekidis Stephanie,Li Xinyuan,Kass-Gergi Sara,Crespo Maria M.,Meyer Nuala J.,Mitchell Michael J.,Basal Maria C.,Wong Joanna,Cosgriff Christopher V.,Planer Joseph D.,Weiner Aaron I.,Gentile Maria E.,Xue Lulu,Vaughan Andrew E.,Cantu Edward,Holcomb Nicolas P.,Christie Jason D..Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-Inflammatory Macrophage Activation[EB/OL].(2025-03-28)[2025-05-04].https://www.biorxiv.org/content/10.1101/2023.05.25.541966.点此复制
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