Vascular Endothelial-derived SPARCL1 Exacerbates Viral Pneumonia Through Pro-inflammatory Macrophage Activation

Overview

Journal Nat Commun

Specialty Biology

Date 2024 May 18

PMID 38762489

Authors

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

Andrew E Vaughan

Affiliations

Soon will be listed here.

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.

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References

Montazersaheb S, Hosseiniyan Khatibi S, Hejazi M, Tarhriz V, Farjami A, Ghasemian Sorbeni F . COVID-19 infection: an overview on cytokine storm and related interventions. Virol J. 2022; 19(1):92. PMC: 9134144. DOI: 10.1186/s12985-022-01814-1. View

Zhao G, Xue L, Weiner A, Gong N, Adams-Tzivelekidis S, Wong J . TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue. Sci Transl Med. 2024; 16(732):eadg6229. DOI: 10.1126/scitranslmed.adg6229. View

van de Veerdonk F, Giamarellos-Bourboulis E, Pickkers P, Derde L, Leavis H, van Crevel R . A guide to immunotherapy for COVID-19. Nat Med. 2022; 28(1):39-50. DOI: 10.1038/s41591-021-01643-9. View

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

Lee J, Bhang D, Beede A, Huang T, Stripp B, Bloch K . Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell. 2014; 156(3):440-55. PMC: 3951122. DOI: 10.1016/j.cell.2013.12.039. View

Ramsey C, Kumar A . H1N1: viral pneumonia as a cause of acute respiratory distress syndrome. Curr Opin Crit Care. 2010; 17(1):64-71. DOI: 10.1097/MCC.0b013e3283427259. View

Ellis L, Cain M, Hutchison V, Flodby P, Crandall E, Borok Z . Epithelial Vegfa Specifies a Distinct Endothelial Population in the Mouse Lung. Dev Cell. 2020; 52(5):617-630.e6. PMC: 7170573. DOI: 10.1016/j.devcel.2020.01.009. View

Toda G, Yamauchi T, Kadowaki T, Ueki K . Preparation and culture of bone marrow-derived macrophages from mice for functional analysis. STAR Protoc. 2021; 2(1):100246. PMC: 7797923. DOI: 10.1016/j.xpro.2020.100246. View

Katsura H, Kobayashi Y, Tata P, Hogan B . IL-1 and TNFα Contribute to the Inflammatory Niche to Enhance Alveolar Regeneration. Stem Cell Reports. 2019; 12(4):657-666. PMC: 6450459. DOI: 10.1016/j.stemcr.2019.02.013. View

10.

Sheu C, Gong M, Zhai R, Bajwa E, Chen F, Thompson B . The influence of infection sites on development and mortality of ARDS. Intensive Care Med. 2010; 36(6):963-70. PMC: 3116923. DOI: 10.1007/s00134-010-1851-3. View

11.

Armstrong S, Darwish I, Lee W . Endothelial activation and dysfunction in the pathogenesis of influenza A virus infection. Virulence. 2013; 4(6):537-42. PMC: 5359731. DOI: 10.4161/viru.25779. View

12.

Liu P, Li Y, Li M, Zhou H, Zhang H, Zhang Y . Endothelial Shp2 deficiency controls alternative activation of macrophage preventing radiation-induced lung injury through notch signaling. iScience. 2022; 25(3):103867. PMC: 8859005. DOI: 10.1016/j.isci.2022.103867. View

13.

Zhang L, Gao S, White Z, Dai Y, Malik A, Rehman J . Single-cell transcriptomic profiling of lung endothelial cells identifies dynamic inflammatory and regenerative subpopulations. JCI Insight. 2022; 7(11). PMC: 9220950. DOI: 10.1172/jci.insight.158079. View

14.

Niethamer T, Stabler C, Leach J, Zepp J, Morley M, Babu A . Defining the role of pulmonary endothelial cell heterogeneity in the response to acute lung injury. Elife. 2020; 9. PMC: 7176435. DOI: 10.7554/eLife.53072. View

15.

Ding B, Nolan D, Guo P, Babazadeh A, Cao Z, Rosenwaks Z . Endothelial-derived angiocrine signals induce and sustain regenerative lung alveolarization. Cell. 2011; 147(3):539-53. PMC: 3228268. DOI: 10.1016/j.cell.2011.10.003. View

16.

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L . Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 384(8):693-704. PMC: 7383595. DOI: 10.1056/NEJMoa2021436. View

17.

Nakatsumi H, Matsumoto M, Nakayama K . Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages. Cell Rep. 2017; 21(9):2471-2486. DOI: 10.1016/j.celrep.2017.11.014. View

18.

Kawai T, Akira S . Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med. 2007; 13(11):460-9. DOI: 10.1016/j.molmed.2007.09.002. View

19.

Kalucka J, de Rooij L, Goveia J, Rohlenova K, Dumas S, Meta E . Single-Cell Transcriptome Atlas of Murine Endothelial Cells. Cell. 2020; 180(4):764-779.e20. DOI: 10.1016/j.cell.2020.01.015. View

20.

Adikusuma F, Pfitzner C, Thomas P . Versatile single-step-assembly CRISPR/Cas9 vectors for dual gRNA expression. PLoS One. 2017; 12(12):e0187236. PMC: 5718404. DOI: 10.1371/journal.pone.0187236. View