Aychek Tegest, Mildner Alexander, Yona Simon, Kim Ki-Wook, Lampl Nardy, Reich-Zeliger Shlomit, Boon Louis, Yogev Nir, Waisman Ari, Cua Daniel J, Jung Steffen
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Bioceros, Yalelaan 46, 3584 CM Utrecht, The Netherlands.
Nat Commun. 2015 Mar 12;6:6525. doi: 10.1038/ncomms7525.
Gut homeostasis and mucosal immune defense rely on the differential contributions of dendritic cells (DC) and macrophages. Here we show that colonic CX3CR1(+) mononuclear phagocytes are critical inducers of the innate response to Citrobacter rodentium infection. Specifically, the absence of IL-23 expression in macrophages or CD11b(+) DC results in the impairment of IL-22 production and in acute lethality. Highlighting immunopathology as a death cause, infected animals are rescued by the neutralization of IL-12 or IFNγ. Moreover, mice are also protected when the CD103(+) CD11b(-) DC compartment is rendered deficient for IL-12 production. We show that IL-12 production by colonic CD103(+) CD11b(-) DC is repressed by IL-23. Collectively, in addition to its role in inducing IL-22 production, macrophage-derived or CD103(-) CD11b(+) DC-derived IL-23 is required to negatively control the otherwise deleterious production of IL-12 by CD103(+) CD11b(-) DC. Impairment of this critical mononuclear phagocyte crosstalk results in the generation of IFNγ-producing former TH17 cells and fatal immunopathology.
肠道稳态和黏膜免疫防御依赖于树突状细胞（DC）和巨噬细胞的不同作用。我们在此表明，结肠CX3CR1(+)单核吞噬细胞是对鼠柠檬酸杆菌感染先天反应的关键诱导因子。具体而言，巨噬细胞或CD11b(+) DC中IL-23表达的缺失会导致IL-22产生受损和急性致死性。以免疫病理学作为死亡原因，通过中和IL-12或IFNγ可挽救受感染动物。此外，当CD103(+) CD11b(-) DC区室的IL-12产生缺陷时，小鼠也受到保护。我们表明，结肠CD103(+) CD11b(-) DC产生的IL-12受到IL-23的抑制。总体而言，除了其在诱导IL-22产生中的作用外，巨噬细胞来源或CD103(-) CD11b(+) DC来源的IL-23对于负向控制CD103(+) CD11b(-) DC产生的否则有害的IL-12是必需的。这种关键的单核吞噬细胞串扰的损害会导致产生产生IFNγ的前TH17细胞和致命的免疫病理学。
