TY - JOUR
T1 - Defective regulation of CXCR2 facilitates neutrophil release from bone marrow causing spontaneous inflammation in severely NF-κB-deficient mice
AU - Von Vietinghoff, Sibylle
AU - Asagiri, Masataka
AU - Azar, David
AU - Hoffmann, Alexander
AU - Ley, Klaus
PY - 2010/7/1
Y1 - 2010/7/1
N2 - 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-/-Nfkb1-/-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.
AB - 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-/-Nfkb1-/-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.
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U2 - 10.4049/jimmunol.1000339
DO - 10.4049/jimmunol.1000339
M3 - Article
C2 - 20519647
AN - SCOPUS:77956214915
SN - 0022-1767
VL - 185
SP - 670
EP - 678
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -