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

NF-kappa B is a major regulator of innate and adaptive immunity. Neutrophilic granulocytes (neutrophils) constitutively express RelA/p65 (Rela), c-Rel (Crel), and p50 (Nf kappa b1) but not p52 (Nf kappa b2) subunits. In this paper, we describe Crel(-/-)Nf kappa b1(-/-)Rela(+/-) mice that have the most severe genetic neutrophil NF-kappa B deficiency compatible with life, Rela(-/-) mice being embryonic lethal. Crel(-/-) Nf kappa b1(-/-)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(-/-)Nf kappa b1(-/-)Rela(+/-) bone marrow was transferred into wild-type mice, but mixed bone marrow chimeras receiving wild-type and Crel(-/-)Nf kappa b1(-/-)Rela(+/-) bone marrow showed normal circulating neutrophil numbers, excluding an intrinsic proliferation advantage. In mixed bone marrow chimeras, Crel(-/-)Nf kappa b1(-/-)Rela(+/-) neutrophils were preferentially mobilized from the bone marrow in response to CXCL1 injection, LPS-induced lung inflammation, and thioglycollate-induced peritonitis. Crel(-/-)Nf kappa b1(-/-)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(-/-)Nf kappa b1(-/-)Rela(+/-) neutrophils in peritonitis in mixed chimeric mice and neutrophilia in Crel(-/-)Nf kappa b1(-/-)Rela(+/-) mice. We conclude that severe NF-kappa B 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-kappa B inhibitors for the treatment of inflammatory diseases. The Journal of Immunology, 2010, 185: 670-678.