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.
Highlights
Type 2 immunity plays a crucial role in host defense against nematode infection and pathogenesis of atopic diseases such as allergy and asthma
Both IL-25 and IL-33 are epitheliumderived cytokines that are important in initiating type 2 immunity through the induction of downstream IL-4/IL-5/IL-13 [1,2], the specific cells that respond to these cytokines have not been fully identified
bone marrow-derived macrophages (BMDM) were differentiated from precursors with M-CSF for 7 days and are generally considered to be a pure population of mature macrophages [19]. Quantitative Polymerase Chain reaction (qPCR) showed the expression of IL-25R (IL-17RA and RB) and IL-33R (IL-1RL1 and IL-1Racp) were detected readily in BMDM, suggesting these cells can respond to IL-25 and IL-33
Summary
Type 2 immunity plays a crucial role in host defense against nematode infection and pathogenesis of atopic diseases such as allergy and asthma. As opposed to the well-established Th1 immunity, the cellular and molecular events occurring at the early phase of type 2 immunity remain unclear despite intensive research in recent years. Both IL-25 and IL-33 are epitheliumderived cytokines that are important in initiating type 2 immunity through the induction of downstream IL-4/IL-5/IL-13 [1,2], the specific cells that respond to these cytokines have not been fully identified. Several novel innate cell populations including ‘‘natural helper cells’’, ‘‘nuocytes’’, and ‘‘innate helper type 2 cells’’, collectively referred as type 2 innate lymphoid cells (ILC2), were shown to respond to IL-25/IL-33 and produce type 2 cytokines [4,5,6,7]. It is noteworthy that most of these cell types are observed rarely in tissues under steady-state conditions
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