Credit: GETTY

Neutrophils have an important role in immune surveillance, but they also contribute to tissue damage. Therefore, the steady-state recruitment of neutrophils from the bone marrow to tissues must be tightly regulated. In this study, the authors propose a feedback circuit — involving CXC-chemokine receptor 2 (CXCR2), its ligand CXC-chemokine ligand 5 (CXCL5), interleukin-17A (IL-17A) and granulocyte colony-stimulating factor (G-CSF) — that controls neutrophil homeostasis in the steady state.

Granulopoiesis and the recruitment of neutrophils from the bone marrow are stimulated by G-CSF and depend, in part, on CXCR2 expression. Furthermore, IL-17A, which can induce G-CSF production, is a potent signal for neutrophil mobilization. In this study, the authors showed that Cxcr2−/− mice had greatly increased neutrophil numbers in the bone marrow and blood compared with control mice. Interestingly, the levels of G-CSF and IL-17A were increased in the blood of Cxcr2−/− mice, and transfer of CXCR2+ neutrophils into these mice reduced G-CSF and IL-17A expression to basal levels. In addition, IL-17A expression was increased in the lungs, terminal ileum and spleen in Cxcr2−/− mice compared with the expression levels in wild-type mice. So, CXCR2+ neutrophils control the expression of the factors involved in their mobilization.

Cxcl5−/− mice also had increased neutrophil numbers in the bone marrow and blood and increased levels of Il17a mRNA in the gut (but not the lungs), suggesting that the CXCL5–CXCR2 pathway in neutrophils can regulate IL-17A levels in the gut. Using bone marrow chimeric mice, the authors showed that gut-resident cells (identified as enterocytes) produce CXCL5 under basal conditions. Furthermore, loss of CXCL5 expression by tissue-resident cells resulted in an increase in neutrophil numbers in the bone marrow, suggesting that constitutive CXCL5 expression in the gut helps to regulate neutrophil numbers in the steady state.

Antibody-mediated inhibition of IL-17A in Cxcr2−/− or Cxcl5−/− mice reduced neutrophil numbers in the bone marrow and G-CSF levels in the blood, suggesting that CXCR2 and CXCL5 regulate the expression of IL-17A and G-CSF to maintain neutrophil homeostasis. Finally, antibiotic-mediated depletion of commensal bacteria in Cxcr2−/− mice decreased neutrophil numbers in the bone marrow and blood and lowered the plasma levels of IL-17A and G-CSF.

So, activation of CXCR2 on neutrophils by CXCL5 derived from gut-resident cells is required to negatively regulate the expression of IL-17A and G-CSF, factors that promote granulopoiesis and neutrophil egress from the bone marrow and thus facilitate the migration of neutrophils to tissues. In the absence of this CXCR2-dependent negative feedback circuit, commensal bacteria can promote the expression of IL-17A and G-CSF.