IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice

被引:78
作者
Smith, Emily [1 ]
Zarbock, Alexander [1 ,5 ,6 ]
Stark, Matthew A. [2 ,3 ]
Burcin, Tracy L. [2 ,3 ]
Bruce, Anthony C. [2 ,3 ]
Foley, Patricia [4 ]
Ley, Klaus
机构
[1] Univ Virginia, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA
[2] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA
[3] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA
[4] Univ Virginia, Off Vice President Res & Grad Studies, Charlottesville, VA 22908 USA
[5] Univ Munster, Dept Anesthesiol & Crit Care Med, Munster, Germany
[6] La Jolla Inst Allergy & Immunol, Div Inflammat Biol, La Jolla, CA 92037 USA
关键词
D O I
10.4049/jimmunol.179.12.8274
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IL-23 is secreted by macrophages and dendritic cells in response to microbial products and inflammatory cytokines. IL-23 is a heterodimer composed of the unique IL-23p19 subunit linked to the common p40 subunit that it shares with IL-12. IL-23 is implicated in autoimmune diseases, where it supports the expansion of IL-17A-producing CD4(+) Th17 cells. IL-23 also regulates granulopoiesis in a neutrostat regulatory feedback loop through IL-17A-producing neutrophil regulatory (Tn) cells, most of which express gamma delta TCR. This homeostatic system is disrupted in mice lacking adhesion molecules like beta(2)-integrins (Itgb2(-/-)) which have defective neutrophil trafficking and neutrophilia. To test the role of IL-23 in the homeostatic regulation of circulating neutrophil numbers, we measured blood neutrophil numbers in p40-deficient (IL12b(-/-)) mice and found them reduced compared with wild-type mice. IL12b(-/-)Itgb2(-/-) mice, lacking beta(2)-integrins, IL-12, and IL-23 showed significantly blunted neutrophilia compared with Itgb2(-/-) mice. Treatment of both IL12b(-/-) and IL12b(-/-)Itgb2(-/-) mice with IL-23, but not IL-12, restored circulating neutrophil counts. Serum levels of IL-17A were readily detectable in Itgb2(-/-) mice, but not in IL12b(-/-)Itgb2(-/-) mice, suggesting that IL-17A production is reduced when IL-23 is absent. Similarly, tissue mRNA expression of IL-17A was reduced in IL12b(-/-)Itgb2(-/-) mice compared with Itgb2(-/-) controls. The total number of CD3(+) IL-17A-producing Tn cells were significantly reduced in the spleen and lamina propria of IL12b(-/-)Itgb2(-/-) mice, with the largest reduction found in gamma delta(+) T cells. Our results suggest a prominent role of IL-23 in the regulation of granulopoiesis and the prevalence of IL-17A-producing Tn cells.
引用
收藏
页码:8274 / 8279
页数:6
相关论文
共 49 条
[1]   Interleukin-12, a key cytokine in Th1-mediated autoimmune diseases [J].
Adorini, L .
CELLULAR AND MOLECULAR LIFE SCIENCES, 1999, 55 (12) :1610-1625
[2]   Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17 [J].
Aggarwal, S ;
Ghilardi, N ;
Xie, MH ;
de Sauvage, FJ ;
Gurney, AL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (03) :1910-1914
[3]   Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12 [J].
Becher, B ;
Durell, BG ;
Noelle, RJ .
JOURNAL OF CLINICAL INVESTIGATION, 2002, 110 (04) :493-497
[4]   Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis [J].
Becker, Christoph ;
Dornhoff, Heike ;
Neufert, Clemens ;
Fantini, Massimo C. ;
Wirtz, Stefan ;
Huebner, Sabine ;
Nikolaev, Alexei ;
Lehr, Hans-Anton ;
Murphy, Andrew J. ;
Valenzuela, David M. ;
Yancopoulos, George D. ;
Galle, Peter R. ;
Karow, Margaret ;
Neurath, Markus F. .
JOURNAL OF IMMUNOLOGY, 2006, 177 (05) :2760-2764
[5]   Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells [J].
Bettelli, E ;
Carrier, YJ ;
Gao, WD ;
Korn, T ;
Strom, TB ;
Oukka, M ;
Weiner, HL ;
Kuchroo, VK .
NATURE, 2006, 441 (7090) :235-238
[6]   Prevention of experimental autoimmune encephalomyelitis in common marmosets using an anti-IL-12p4O monoclonal antibody [J].
Brok, HPM ;
van Meurs, M ;
Blezer, E ;
Schantz, A ;
Peritt, D ;
Treacy, G ;
Laman, JD ;
Bauer, J ;
't Hart, BA .
JOURNAL OF IMMUNOLOGY, 2002, 169 (11) :6554-6563
[7]   Th1 cells regulate hematopoietic progenitor cell homeostasis by production of oncostatin M [J].
Broxmeyer, HE ;
Bruns, HA ;
Zhang, SM ;
Cooper, S ;
Hangoc, G ;
McKenzie, ANJ ;
Dent, AL ;
Schindler, U ;
Naeger, LK ;
Hoey, T ;
Kaplan, MH .
IMMUNITY, 2002, 16 (06) :815-825
[8]   Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis [J].
Chen, Y ;
Langrish, CL ;
Mckenzie, B ;
Joyce-Shaikh, B ;
Stumhofer, JS ;
McClanahan, T ;
Blumenschein, W ;
Churakovsa, T ;
Low, J ;
Presta, L ;
Hunter, CA ;
Kastelein, RA ;
Cua, DJ .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (05) :1317-1326
[9]   STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice [J].
Cho, Mi-La ;
Kang, Jung-Won ;
Moon, Young-Mee ;
Nam, Hyo-Jung ;
Jhun, Joo-Yeon ;
Heo, Seong-Beom ;
Jin, Hyun-Tak ;
Min, So-Youn ;
Ju, Ji-Hyeon ;
Park, Kyung-Su ;
Cho, Young-Gyu ;
Yoon, Chong-Hyeon ;
Park, Sung-Hwan ;
Sung, Young-Chul ;
Kim, Ho-Youn .
JOURNAL OF IMMUNOLOGY, 2006, 176 (09) :5652-5661
[10]   Expression and regulation of IL-22 in the IL-17-producing CD4+T lymphocytes [J].
Chung, Yeonseok ;
Yang, Xuexian ;
Chang, Seon Hee ;
Ma, Li ;
Tian, Qiang ;
Dong, Chen .
CELL RESEARCH, 2006, 16 (11) :902-907