Increased Expression of CXCL6 in Secretory Cells Drives Fibroblast Collagen Synthesis and is Associated With Increased Mortality in Idiopathic Pulmonary Fibrosis

RATIONALE: Recent data suggest that the localization of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover if chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF. METHODS: We analyzed whole lung and single-cell transcriptomic data obtained from patients with IPF. We also measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface (ALI) cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signaling on fibroblast function. RESULTS: By analysis of both whole lung transcriptomics, protein, and BAL, we discovered that CXCL6-a member of the IL-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 homolog) 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 over-expression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts. CONCLUSIONS: CXCL6 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 localization of airway epithelial cells in IPF.

• Bahudhanapati, H.
• Tan, J.
• Apel, R. M.
• Seeliger, B.
• Schupp, J.
• Li, X.
• Sullivan, D. I.
• Sembrat, J.
• Rojas, M.
• Tabib, T.
• Valenzi, E.
• Lafyatis, R.
• Mitash, N.
• Pineda, R. H.
• Jawale, C.
• Peroumal, D.
• Biswas, P.
• Tedrow, J.
• Adams, T.
• Kaminski, N.
• Wuyts, W. A.
• McDyer, J. F.
• Gibson, K. F.
• Alder, J. K.
• Königshoff, M.
• Zhang, Y.
• Nouraie, M.
• Prasse, A.
• Kass, D. J.