Defective regulation of CXCR2 facilitates neutrophil release from bone marrow causing spontaneous inflammation in severely NF-kappa B-deficient mice.
NF-kappaB is a major regulator of innate and adaptive immunity. Neutrophilic granulocytes (neutrophils) constitutively express RelA/p65 (Rela), c-Rel (Crel), and p50 (Nfkappab1) but not p52 (Nfkappab2) subunits. In this paper, we describe Crel(-/-)Nfkappab1(-/-)Rela(+/-) mice that have the most severe genetic neutrophil NF-kappaB deficiency compatible with life, Rela(-/-) mice being embryonic lethal. Crel(-/-)Nfkappab1(-/-)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(-/-)Nfkappab1(-/-)Rela(+/-) bone marrow was transferred into wild-type mice, but mixed bone marrow chimeras receiving wild-type and Crel(-/-)Nfkappab1(-/-)Rela(+/-) bone marrow showed normal circulating neutrophil numbers, excluding an intrinsic proliferation advantage. In mixed bone marrow chimeras, Crel(-/-)Nfkappab1(-/-)Rela(+/-) neutrophils were preferentially mobilized from the bone marrow in response to CXCL1 injection, LPS-induced lung inflammation, and thioglycollate-induced peritonitis. Crel(-/-)Nfkappab1(-/-)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(-/-)Nfkappab1(-/-)Rela(+/-) neutrophils in peritonitis in mixed chimeric mice and neutrophilia in Crel(-/-)Nfkappab1(-/-)Rela(+/-) mice. We conclude that severe NF-kappaB 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-kappaB inhibitors for the treatment of inflammatory diseases.
von Vietinghoff
Sibylle
S
Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92122, USA. sibyllevvietinghoff@gmx.de
Asagiri
Masataka
M
Azar
David
D
Hoffmann
Alexander
A
Ley
Klaus
K
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005838:Genotype; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007958:Leukocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000172:deficiency* / Q000235:genetics; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051996:Transcription Factor RelA / Q000172:deficiency / Q000235:genetics
D052002:NF-kappa B p50 Subunit; D020569:Proto-Oncogene Proteins c-rel; D023063:Receptors, Interleukin-8B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA