[Show abstract][Hide abstract] ABSTRACT: Lymphocyte recruitment to intestinal tissues depends on β(7) integrins. In this study, we studied disease severity and lymphocyte recruitment into the small intestine in SAMP1/YitFc mice, which develop chronic ileitis with similarity to human Crohn's disease. To assess the role of β(7) integrins in chronic ileitis, we generated SAMP1/YitFc lacking β(7) integrins (SAMP1/YitFc Itgb7(-/-)) using a congenic strain developed via marker-assisted selection. We analyzed ileal inflammation in SAMP1/YitFc and SAMP1/YitFc Itgb7(-/-) mice by histopathology and the distribution of T and B lymphocytes in the mesenteric lymph nodes (MLNs) by flow cytometry. Short-term (18 h) adoptive transfer experiments were used to study the in vivo homing capacity of T and B lymphocytes. In both young (<20 wk) and old (20-50 wk) SAMP1/YitFc Itgb7(-/-) mice, ileitis was reduced by 30-50% compared with SAMP1/YitFc mice. SAMP1/YitFc Itgb7(-/-) mice showed a dramatic 67% reduction in the size of their MLNs, which was caused by a 85% reduction in lymphocyte numbers and reduced short-term B cell homing. Flow cytometric analysis revealed a highly significant decrease in the percentage of B cells in MLNs of SAMP1/YitFc Itgb7(-/-) mice. Cotransfer of SAMP1/YitFc MLN B cells but not SAMP1/YitFc Itgb7(-/-) MLN B cells along with CD4(+) T cells resulted in exacerbated ileitis severity in SCID mice. Our findings suggest that β(7) integrins play an essential role in spontaneous chronic ileitis in vivo by promoting homing of disease-exacerbating B cells to MLNs and other intestinal tissues.
Full-text · Article · Oct 2010 · The Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: 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.
Full-text · Article · Jul 2010 · The Journal of Immunology