title: Macrophages as IL-25/IL-33-responsive cells play an important role in the induction of type 2 immunity.
abstract: Type 2 immunity is essential for host protection against nematode infection but is detrimental in allergic inflammation or asthma. There is a major research focus on the effector molecules and specific cell types involved in the initiation of type 2 immunity. Recent work has implicated an important role of epithelial-derived cytokines, IL-25 and IL-33, acting on innate immune cells that are believed to be the initial sources of type 2 cytokines IL-4/IL-5/IL-13. The identities of the cell types that mediate the effects of IL-25/IL-33, however, remain to be fully elucidated. In the present study, we demonstrate that macrophages as IL-25/IL-33-responsive cells play an important role in inducing type 2 immunity using both in vitro and in vivo approaches. Macrophages produced type 2 cytokines IL-5 and IL-13 in response to the stimulation of IL-25/IL-33 in vitro, or were the IL-13-producing cells in mice administrated with exogenous IL-33 or infected with Heligmosomoides bakeri. In addition, IL-33 induced alternative activation of macrophages primarily through autocrine IL-13 activating the IL-4Rα-STAT6 pathway. Moreover, depletion of macrophages attenuated the IL-25/IL-33-induced type 2 immunity in mice, while adoptive transfer of IL-33-activated macrophages into mice with a chronic Heligmosomoides bakeri infection induced worm expulsion accompanied by a potent type 2 protective immune response. Thus, macrophages represent a unique population of the innate immune cells pivotal to type 2 immunity and a potential therapeutic target in controlling type 2 immunity-mediated inflammatory pathologies.
authors.affiliation: Department of Medicine and the Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Yang
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Grinchuk
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bohl
authors.forename: Rex
authors.initials: R
authors.lastname: Sun
authors.forename: Luigi
authors.initials: L
authors.lastname: Notari
authors.forename: Shu
authors.initials: S
authors.lastname: Yan
authors.forename: Thirumalai
authors.initials: T
authors.lastname: Ramalingam
authors.forename: Achsah D
authors.initials: AD
authors.lastname: Keegan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Terez
authors.initials: T
authors.lastname: Shea-Donohue
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D018793:Interleukin-13 / Q000096:biosynthesis; D000067596:Interleukin-33; D007378:Interleukins / Q000008:administration & dosage / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009349:Nematode Infections / Q000276:immunology / Q000517:prevention & control
chemical_list: D016207:Cytokines; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; C442281:Mydgf protein, mouse
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