CXCL-1/KC collaborates with CXCL-2/MIP2 to regulate granulopoiesis and recruitment in pneumococcal pneumonia

Abstract

Abstract Streptococcus pneumoniae remains as a leading cause of community-acquired pneumonia in the U.S. and world. Leukocytes (neutrophils) recruitment to the lungs is critical step in the host defense against pneumococcal infections. CXCL-1/KC is sufficient to induce neutrophil influx in numerous bacterial lung infections, but precise mechanism of how it regulates recruitment to the lungs remains unexplored. Here, we used a mouse model of pneumococcal pneumonia to investigate the role of CXCL-1 in neutrophil granulopoiesis, recruitment, and host defense. CXCL-1 knockout and their wild type controls were infected intratracheally with S. pneumoniae. Survival, leukocyte influx, cytokines/chemokines in bronchoalveolar lavage fluid, and bacterial burdens in lungs and other organs were quantified. Flow cytometry was performed to study different stages of neutrophil granulopoiesis according to their levels of c-Kit and Ly6G expression. Recombinant CXCL-2/MIP2 was administered to rescue neutrophil recruitment in CXCL-1 knockout mice. We here demonstrate that CXCL-1 modulates rapid neutrophil influx, restricts bacterial burden in lungs, regulates production of cytokines/chemokines, and improves host survival. Flow cytometry analysis revealed CXCL-1 is involved in efficient amplification of early neutrophil precursor and release of mature neutrophils from bone marrow. Furthermore, CXCL-2 treatment post-pneumonia corrected the impairment in host defense through increased neutrophil influx in CXCL -1 knockout mice. These results suggest CXCL-1 mediates granulopoiesis and recruitment of neutrophil, and modulation of its activity presents a promising avenue for development of therapeutics against pneumococcal pneumonia.