Increased expression of CXCL6 in secretory cells drives fibroblast collagen synthesis and is associated with increased mortality in idiopathic pulmonary fibrosis

Author:

Bahudhanapati Harinath,Tan Jiangning,Apel Rosa Marie,Seeliger Benjamin,Schupp JonasORCID,Li Xiaoyun,Sullivan Daniel I.,Sembrat John,Rojas Mauricio,Tabib Tracy,Valenzi Eleanor,Lafyatis RobertORCID,Mitash NilayORCID,Hernandez Pineda RicardoORCID,Jawale Chetan,Peroumal DoureradjouORCID,Biswas Partha,Tedrow John,Adams TaylorORCID,Kaminski NaftaliORCID,Wuyts Wim A.ORCID,McDyer John F.,Gibson Kevin F.,Alder Jonathan K.ORCID,Königshoff MelanieORCID,Zhang YingzeORCID,Nouraie MehdiORCID,Prasse AntjeORCID,Kass Daniel J.ORCID

Abstract

RationaleRecent data suggest that the localisation of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover whether chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF.MethodsWe analysed whole lung and single-cell transcriptomic data obtained from patients with IPF. In addition, we measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air–liquid interface cultures. We employedex vivodonor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signalling on fibroblast function.ResultsBy analysis of whole-lung transcriptomics, protein and BAL, we discovered that CXCL6 (a member of the interleukin-8 family) was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (hazard ratio of death or progression 1.89, 95% CI 1.16–3.08; n=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while overexpression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts.ConclusionsCXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localisation of airway epithelial cells in IPF.

Funder

Daniel Kass

Publisher

European Respiratory Society (ERS)

Subject

Pulmonary and Respiratory Medicine

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