CXCL5-dependent neutrophil recruitment harms lung barrier function in acute lung injury

Abstract

Background: Neutrophils are important components of innate immune responses against bacterial infections, yet excessive neutrophil responses might result in life-threatening lung injury. Neutrophil recruitment to sites of inflammation is partly mediated by the chemokine receptor CXCR2. Chemokines, like the CXCR2 ligands, which target a shared receptor, are generally considered redundant. However, we and others described their individual spatial and temporal regulation patterns. Aims and Objectives: To investigate if pneumocyte-derived ligand CXCL5 plays a superordinate role in acute lung injury. Methods: Murine models of ventilator-induced lung injury (VILI) and pneumococcal pneumonia in CXCL5-deficient (Cxcl5‒/‒) and wild-type (WT) mice. Results: Following mechanical ventilation, absence of CXCL5 resulted in reduced alveolar neutrophil recruitment and decreased vascular leakage. Depletion of neutrophils prior to VILI confirmed their impact on lung barrier disruption. In line, in response to pulmonary Streptococcus pneumoniae infection, neutrophil recruitment significantly depended on CXCL5 signaling. Reduced neutrophil numbers resulted in increased bacterial burden in Cxcl5‒/‒ compared to WT mice without affecting overall survival rates. Notably, despite elevated bacterial burden, vascular leakage was reduced in the absence of CXCL5. Conclusions: Our results confirm the non-redundancy of CXCR2 ligands and highlight the importance of CXCL5 in neutrophil recruitment and development of lung barrier failure in acute lung injury. Targeting CXCL5 may possibly provide a therapeutic perspective in pneumonia and mechanical ventilation.