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

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 2; pp. 582 - 594.e10
• Main Authors: Peng, Hui, Ning, Huan, Wang, Qinghong, Lu, Wenbao, Chang, Yingzi, Wang, Tony T., Lai, Jinping, Kolattukudy, Pappachan E., Hou, Rong, Hoft, Daniel F., Dykewicz, Mark S., Liu, Jianguo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-08-2018
• Subjects: asthma; Gata3; IL-13; IL-4; IL-5; MCPIP1; mRNA decay; Notch; RNA-Binding protein; TH2 cells; TCR; PAS; DLL; MCPIP1; HDM; ILC2; TH2 cells; UTR; shRNA; MCPIP-1; GSI; WT; mRNA decay; RNA-Binding protein; PMA; CARMA1; H&E; Notch; BALF; IL-4; IL-5; asthma; IL-13; STAT; Gata3; OVA
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.09.031

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.
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.
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.
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.
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.
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