CXCR2 And CXCL5 Regulate IL-17/G-CSF Axis And Neutrophil Homeostasis

Neutrophil homeostasis is critical for maintaining innate immune surveillance under normal conditions. CXCR2 plays a critical role in neutrophil homeostasis, as Cxcr2-/- mice demonstrate mild neutrophilia and severe neutrophil hyperplasia in the bone marrow. We found that neutrophil CXCR2 inhibits the IL-17A/G-CSF axis that regulates neutrophil homeostasis, while enterocyte-derived CXCL5 in the gut, regulates the IL-17/G-CSF axis and contributes to CXCR2-regulated neutrophil homeostasis. CXCL5-regulated neutrophil homeostasis was completely dependent on G-CSF, and inhibition of IL-17A reduced plasma G-CSF concentrations and marrow neutrophil numbers in both Cxcl5-/- and Cxcr2-/- mice. Cxcr2-/- mice express IL-17A, and show increased IL-17A-producing cells in the lung, terminal ileum and spleen, which include conventional Th17 cells, γδ T cells, and innate immune cells. Most IL-17 producing splenocytes were responsive to IL-1β plus IL-23 in vitro. Depletion of commensal microbes by antibiotic treatment markedly decreased IL-17A and G-CSF expression, neutrophilia and marrow myeloid hyperplasia in Cxcr2-/- mice. These data provide insights regarding the critical role of CXCR2, CXCL5 and commensal bacteria in regulating the IL-17/G-CSF axis and neutrophil homeostasis at mucosal sites, which keeps the set point of innate immunity in tight control.