STING inhibitor ameliorates LPS-induced ALI by preventing vascular endothelial cells-mediated immune cells chemotaxis and adhesion.

Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 100956087 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1745-7254 (Electronic) Linking ISSN: 16714083 NLM ISO Abbreviation: Acta Pharmacol Sin Subsets: MEDLINE

Publication: 2009- : New York : Nature Publishing Group
Original Publication: Beijing, China : Science Press, c2000-

Acute Lung Injury*/chemically induced ; Acute Lung Injury*/drug therapy ; Acute Lung Injury*/prevention & control ; Membrane Proteins*/antagonists & inhibitors; Animals ; Cell Adhesion ; Chemokines/metabolism ; Chemotaxis ; Cytokines/metabolism ; Endothelial Cells/metabolism ; Humans ; Lipopolysaccharides/pharmacology ; Lung/pathology ; Mice ; NF-kappa B/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Cell Adhesion Molecule-1/adverse effects ; Vascular Cell Adhesion Molecule-1/metabolism

Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1β, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.
(© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

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Keywords: STING; acute lung injury; chemokines; chemotaxis; inflammatory cytokines; vascular endothelial cells

0 (Chemokines)
0 (Cytokines)
0 (Lipopolysaccharides)
0 (Membrane Proteins)
0 (NF-kappa B)
0 (STING1 protein, human)
0 (Tumor Necrosis Factor-alpha)
0 (Vascular Cell Adhesion Molecule-1)

Date Created: 20211215 Date Completed: 20220803 Latest Revision: 20230802

20240829

PMC9343420

10.1038/s41401-021-00813-2

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