Monocyte chemotactic protein–induced protein 1 controls allergic airway inflammation by suppressing IL-5–producing TH2 cells through the Notch/Gata3 pathway - 04/08/18
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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : RNA-Binding protein, MCPIP1, mRNA decay, TH2 cells, IL-4, IL-5, IL-13, Gata3, Notch, asthma
Abbreviations used : BALF, CARMA1, DLL, GSI, HDM, H&E, ILC2, MCPIP-1, OVA, PAS, PMA, shRNA, STAT, TCR, UTR, WT
Plan
| Supported by the National Cancer Institute of the National Institutes of Health under award no. R01CA163808 (to J.L.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. |
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| Disclosure of potential conflict of interest: T. T. Wang's institution received a grant from the National Institute of Diabetes and Digestive and Kidney Disease for this work. M. S. Dykewicz personally received consultant fees from Alcon and Merck for other works. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 2
P. 582 - août 2018 Retour au numéro
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