The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation

Morris Nechama,Robert S Welner,Xiao Zhen Zhou,Iddo Z Ben-Dov,Kun Ping Lu,Shuo Wei,Elliot Israel,Cheng-Yu Tsai,John M Asara,Kyle F Nelson,Mohamed S Arredouani,Jeahoo Kwon,Chun-Hau Chen,Linda K Nicholson,Koichi S Kobayashi,Adrian Tun Kyi

doi:10.1038/s41467-018-03886-6

Abstract

Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation.

Highlights

Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity
interleukin receptor associated kinase M (IRAK-M) is traditionally considered as a negative regulator of TLR/IL-1R signaling by trapping interleukin receptor associated kinase 1 (IRAK1) in the activated receptor complex and preventing downstream signaling[31,32]
To assess PIN1 involvement in IL-33 signaling, mouse embryonic fibroblasts (MEFs) derived from PIN1 wild-type (PIN1 + / +, WT) or knockout (PIN1-/, KO) mice were treated with IL-33, and IL-6 production was measured as a proxy for induction of inflammation (Fig. 1b)

Summary

Introduction

Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The IL33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation. Allergic asthma is a T helper type 2 (TH2 type) immune disease, characterized by pulmonary infiltration of specific T helper cells[1,2], and increased secretion of the type 2 cytokines IL-4, -5 and -13. TLR4, predominantly expressed on pulmonary epithelial cells and alveolar macrophages[8], mediates asthma induction by Derp[2], a major allergen of the house dust mite (HDM)[9] The activation of such TLRs by airborne allergens often induces TH2 response[10] via mediators such as interleukin 33 (IL-33), a ligand for IL-1R8,11,12. IL-33 1) activates resident dendritic cells (DC) to induce their maturation critical for allergic airway inflammation[15,16] via DC-stimulated differentiation of vates DCs to Tprcoemllos tienntoaivTeHC2Dc4el+lsT(TceHl2ls polarization)[17], to produce IL-5

Methods

Results

Conclusion