Neutrophil-chemoattractant CXCL5 induces lung barrier permeability in acute lung injury

Abstract

RationaleAcute lung injury is frequently caused by pneumonia, and severity correlates with inflammatory cell recruitment and lung barrier failure. Deciphering drug-targetable pathways is of clinical importance. ObjectivesInvestigation of paracrine and autocrine effects of epithelial-derived chemokine CXCL5 in acute lung injury. MethodsWe assessed the role of CXCL5 and related chemokines in patients with severe pneumonia and primary cells or cell lines challenged with Streptococcus pneumoniae or exposed to mechanical stretch. Furthermore, we evaluated the role of CXCL5 in in vivo models of acute lung injury through use of Cxcl5-deficient mice and in vitro human lung barrier models. ResultsPneumococcal infection and mechanical ventilation were associated with CXCL5 production in human subjects and in mice. CXCL5 was produced by bronchial and alveolar epithelial cells. The alveolar-epithelial barrier was protected in acute lung injury models in Cxcl5-deficient mice, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial, but not endothelial cells in Cxcl5-deficient mice. Accordingly, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells, but not pulmonary microvascular endothelial cells. ConclusionsWe describe a novel function of CXCL5 in acute lung injury. Besides its recognized role in recruiting highly inflammatory cells such as neutrophils, CXCL5 increases alveolar-epithelial barrier permeability. Thus, in severe bacterial pneumonia, targeting of CXCL5 as adjunctive therapy to antibiotics may aid in reducing overshooting inflammation as well as stabilizing lung barrier function.