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IL-8 concurrently promotes idiopathic pulmonary fibrosis mesenchymal progenitor cell senescence and PD-L1 expression enabling escape from immune cell surveillance

IL-8 concurrently promotes idiopathic pulmonary fibrosis mesenchymal progenitor cell senescence... Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease. We discovered fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients that display cell autonomous fibrogenicity and drive fibrotic progression. In a study of the IPF MPC nuclear proteome, we identified DNA damage as one of the most altered functions in IPF MPCs. In prior work we found that IL-8 drives IPF MPC self-renewal. IL-8 can promote replicative stress and DNA damage and induce senescence through the CXCR2 receptor. We hypothesized that IL-8 promotes DNA damage-mediated senescence in IPF MPCs. We show that IL-8 induces DNA damage and promotes IPF MPC senescence. We discovered that IL-8 concurrently promotes senescence and upregulation of the programmed death ligand 1 (PD-L1) in a CXCR2-dependent manner. Disruption of PD-1/PD-L1 interaction promotes NK cell killing of IPF MPCs in vitro and arrests IPF MPC-mediated experimental lung fibrosis in vivo. IHC analysis of IPF lung tissue identifies PD-L1 expressing IPF MPCs co-distributing with NK cells and b-galactosidase positive cells. Our data indicate that IL-8 simultaneously promotes IPF MPC DNA damage-induced senescence and high PDL1 expression enabling IPF MPCs to elude immune cell targeted removal. Disruption of PD1/PDL1 interaction may limit IPF MPC mediated fibrotic progression. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP Lung Cellular and Molecular Physiology The American Physiological Society

IL-8 concurrently promotes idiopathic pulmonary fibrosis mesenchymal progenitor cell senescence and PD-L1 expression enabling escape from immune cell surveillance

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References (46)

ISSN
1040-0605
eISSN
1522-1504
DOI
10.1152/ajplung.00028.2023
Publisher site
See Article on Publisher Site

Abstract

Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease. We discovered fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients that display cell autonomous fibrogenicity and drive fibrotic progression. In a study of the IPF MPC nuclear proteome, we identified DNA damage as one of the most altered functions in IPF MPCs. In prior work we found that IL-8 drives IPF MPC self-renewal. IL-8 can promote replicative stress and DNA damage and induce senescence through the CXCR2 receptor. We hypothesized that IL-8 promotes DNA damage-mediated senescence in IPF MPCs. We show that IL-8 induces DNA damage and promotes IPF MPC senescence. We discovered that IL-8 concurrently promotes senescence and upregulation of the programmed death ligand 1 (PD-L1) in a CXCR2-dependent manner. Disruption of PD-1/PD-L1 interaction promotes NK cell killing of IPF MPCs in vitro and arrests IPF MPC-mediated experimental lung fibrosis in vivo. IHC analysis of IPF lung tissue identifies PD-L1 expressing IPF MPCs co-distributing with NK cells and b-galactosidase positive cells. Our data indicate that IL-8 simultaneously promotes IPF MPC DNA damage-induced senescence and high PDL1 expression enabling IPF MPCs to elude immune cell targeted removal. Disruption of PD1/PDL1 interaction may limit IPF MPC mediated fibrotic progression.

Journal

AJP Lung Cellular and Molecular Physiology – The American Physiological Society

Published: Jun 1, 2023

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