IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice.
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 gammadelta TCR. This homeostatic system is disrupted in mice lacking adhesion molecules like beta2-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 beta2-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 gammadelta+ 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.
Smith
Emily
E
Robert M. Berne Cardiovascular Research Center, Department of Biomedical Engineering, University of Virginia, Charlottesville 22908, USA. es9cy@virginia.edu
Zarbock
Alexander
A
Stark
Matthew A
MA
Burcin
Tracy L
TL
Bruce
Anthony C
AC
Foley
Patricia
P
Ley
Klaus
K
D000818:Animals; D018821:CD18 Antigens / Q000235:genetics; D006706:Homeostasis / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000502:physiology*; D020381:Interleukin-17 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D053759:Interleukin-23 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D009503:Neutropenia / Q000235:genetics*; D009504:Neutrophils / Q000276:immunology*
D018821:CD18 Antigens; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053759:Interleukin-23