Defective Regulation of CXCR2 Facilitates Neutrophil Release from Bone Marrow Causing Spontaneous Inflammation in Severely NF-κB–Deficient Mice

摘要

NF-κB is a major regulator of innate and adaptive immunity. Neutrophilic granulocytes (neutrophils) constitutively express RelA/p65 ( Rela ), c-Rel ( Crel ), and p50 ( Nfκb1 ) but not p52 ( Nfκb2 ) subunits. In this paper, we describe Crel?/?Nfκb1?/?Rela+/? mice that have the most severe genetic neutrophil NF-κB deficiency compatible with life, Rela?/? mice being embryonic lethal. Crel?/?Nfκb1?/?Rela+/? mice developed spontaneous dermal and intestinal inflammation associated with chronic neutrophilia, elevated CXCL1, and G-CSF. The bone marrow contained fewer nucleated cells and was enriched in myeloid progenitor cells. Neutrophilia was preserved when Crel?/?Nfκb1?/?Rela+/? bone marrow was transferred into wild-type mice, but mixed bone marrow chimeras receiving wild-type and Crel?/?Nfκb1?/?Rela+/? bone marrow showed normal circulating neutrophil numbers, excluding an intrinsic proliferation advantage. In mixed bone marrow chimeras, Crel?/?Nfκb1?/?Rela+/? neutrophils were preferentially mobilized from the bone marrow in response to CXCL1 injection, LPS-induced lung inflammation, and thioglycollate-induced peritonitis. Crel?/?Nfκb1?/?Rela+/? neutrophils expressed higher levels of the CXCL1 receptor CXCR2 both under resting and stimulated conditions and failed to downregulate CXCR2 during inflammation. Treatment with an anti-CXCR2 Ab abolished preferential mobilization of Crel?/?Nfκb1?/?Rela+/? neutrophils in peritonitis in mixed chimeric mice and neutrophilia in Crel?/?Nfκb1?/?Rela+/? mice. We conclude that severe NF-κB deficiency facilitates neutrophil mobilization, which causes elevated numbers of preactivated neutrophils in blood and tissues, leading to spontaneous inflammation. These neutrophil effects may limit the usefulness of global NF-κB inhibitors for the treatment of inflammatory diseases.