CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow

TLDR

Neutrophils, key innate immune cells, are kept in balance by regulated bone marrow release, with CXCL12/CXCR4 signaling retaining them and its attenuation prompting circulation entry via unknown mechanisms. The study examined how CXCR2‑binding ELR+ chemokines influence neutrophil trafficking by creating mixed bone marrow chimeras of Cxcr2‑deficient and wild‑type mice. CXCR2‑deficient neutrophils were trapped in bone marrow, and only loss of both CXCR2 and CXCR4 mobilized them, indicating CXCR4 dominates; CXCL1/2 are produced by bone marrow endothelial cells and osteoblasts, with CXCL2 upregulated by G‑CSF, supporting an antagonistic CXCR2/CXCR4 axis controlling neutrophil release.

Abstract

Neutrophils are a major component of the innate immune response. Their homeostasis is maintained, in part, by the regulated release of neutrophils from the bone marrow. Constitutive expression of the chemokine CXCL12 by bone marrow stromal cells provides a key retention signal for neutrophils in the bone marrow through activation of its receptor, CXCR4. Attenuation of CXCR4 signaling leads to entry of neutrophils into the circulation through unknown mechanisms. We investigated the role of CXCR2-binding ELR+ chemokines in neutrophil trafficking using mouse mixed bone marrow chimeras reconstituted with Cxcr2(-/-) and WT cells. In this context, neutrophils lacking CXCR2 were preferentially retained in the bone marrow, a phenotype resembling the congenital disorder myelokathexis, which is characterized by chronic neutropenia. Additionally, transient disruption of CXCR4 failed to mobilize Cxcr2(-/-) neutrophils. However, neutrophils lacking both CXCR2 and CXCR4 displayed constitutive mobilization, showing that CXCR4 plays a dominant role in neutrophil trafficking. With regard to CXCR2 ligands, bone marrow endothelial cells and osteoblasts constitutively expressed the ELR+ chemokines CXCL1 and CXCL2, and CXCL2 expression was induced in endothelial cells during G-CSF-induced neutrophil mobilization. Collectively, these data suggest that CXCR2 signaling is a second chemokine axis that interacts antagonistically with CXCR4 to regulate neutrophil release from the bone marrow.