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* Robert M. Berne Cardiovascular Research Center,
Departments of Biomedical Engineering and Molecular Physiology and Biological Physics, and
Office for the Vice President for Research and Graduate Studies, University of Virginia, Charlottesville, VA 22908;
Department of Anesthesiology and Critical Care Medicine, University of Muenster, Muenster, Germany; and
¶ Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
division of Inflammation Biology, La Jolla Institute for Allergy and Immnology, La Jolla, CA 92037
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 
TCR. This homeostatic system is disrupted in mice lacking adhesion molecules like β2-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 β2-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 + 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HL73361 (to K.L.), T32 GM 08715-01A1 (to M.A.S.), and Deutsche Forschungsgemeinschaft AZ428/2-1 (to A.Z.).
2 Address correspondence and reprint requests to Dr. Emily Smith, Robert M. Berne Cardiovascular Research Center, University of Virginia, P.O. Box 801394, Charlottesville, VA 22908. E-mail address: es9cy{at}virginia.edu
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalitis; WT, wild type; BM, bone marrow; rm, recombinant mouse; MLN, mesenteric lymph node; LP, lamina propria. Tn, neutrophil regulatory T cell; Th17, IL-17 producing cox + T cells; 16-23R, 16-23 receptor; G-CSF, granulocyte-colony stimulating factor.
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