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Monocyte chemotactic protein–induced protein 1 controls allergic airway inflammation by suppressing IL‐5–producing TH2 cells through the Notch/Gata3 pathway

Hui-min Peng,Huan Ning,Qinghong Wang,Wenbao Lu,Yingzi Chang,Tony T. Wang,J. Lai,P. Kolattukudy,R. Hou,D. Hoft,M. Dykewicz,Jianguo Liu

Published 2017 in Journal of Allergy and Clinical Immunology

ABSTRACT

Background: Asthmatic and allergic inflammation is mediated by TH2 cytokines (IL‐4, IL‐5, and IL‐13). Although we have learned much about how TH2 cells are differentiated, the TH2 checkpoint mechanisms remain elusive. Objectives: In this study we investigate how monocyte chemotactic protein–induced protein 1 (MCPIP1; encoded by the Zc3h12a gene) regulates IL‐5–producing TH2 cell differentiation and TH2‐mediated inflammation. Methods: The functions of Zc3h12a−/− CD4 T cells were evaluated by checking the expression of TH2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of Zc3h12a−/− mice was examined with murine asthma models. In addition, antigen‐specific CD4 T cells deficient in MCPIP1 were transferred to wild‐type recipient mice, challenged with ovalbumin (OVA) or house dust mite (HDM), and accessed for TH2 inflammation. Results: Zc3h12a−/− mice have spontaneous severe lung inflammation, with an increase in mainly IL‐5– and IL‐13–producing but not IL‐4–producing TH2 cells in the lung. Mechanistically, differentiation of IL‐5–producing Zc3h12a−/− TH2 cells is mediated through Notch signaling and Gata3 independent of IL‐4. Gata3 mRNA is stabilized in Zc3h12a−/− TH2 cells. MCPIP1 promotes Gata3 mRNA decay through the RNase domain. Furthermore, deletion of MCPIP1 in OVA‐ or HDM‐specific T cells leads to significantly increased TH2‐mediated airway inflammation in OVA or HDM murine models of asthma. Conclusions: Our study reveals that MCPIP1 regulates the development and function of IL‐5–producing TH2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other TH2‐mediated diseases. Graphical abstract: Figure. No caption available.

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