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

Nat Commun. 2018 Apr 23;9(1):1603. doi: 10.1038/s41467-018-03886-6.

Morris Nechama ¹, Jeahoo Kwon ², Shuo Wei ¹, Adrian Tun Kyi ¹, Robert S Welner ¹, Iddo Z Ben-Dov ³, Mohamed S Arredouani ¹, John M Asara ¹, Chun-Hau Chen ¹, Cheng-Yu Tsai ¹, Kyle F Nelson ⁴, Koichi S Kobayashi ⁵, Elliot Israel ⁴, Xiao Zhen Zhou ¹, Linda K Nicholson ⁶, Kun Ping Lu ⁷ ⁸ ⁹

Affiliations

1 Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
2 Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, 14853, USA.
3 Department of Nephrology and Hypertension, Hadassah-Hebrew Medical Center, 91120, Jerusalem, Israel.
4 Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
5 Department of Microbial Pathogenesis & Immunology, Texas A&M Health Science Center, College Station, TX, 77843, USA.
6 Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, 14853, USA. lkn2@cornell.edu.
7 Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. klu@bidmc.harvard.edu.
8 Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. klu@bidmc.harvard.edu.
9 Institute for Translational Medicine, Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Fujian Medical University, Fuzhou, 350108, Fujian, China. klu@bidmc.harvard.edu.

PMID: 29686383 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.

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