Monocyte Chemotactic Protein–Induced Protein 1 Controls Allergic Airway Inflammation By Suppressing Il-5–Producing TH2 Cells Through The Notch/Gata3 Pathway

Keywords

asthma; Gata3; IL-13; IL-4; IL-5; MCPIP1; mRNA decay; Notch; RNA-Binding protein; T 2 cells H

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.

Publication Date

8-1-2018

Publication Title

Journal of Allergy and Clinical Immunology

Volume

142

Issue

2

Number of Pages

582-5940000000000

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.jaci.2017.09.031

Socpus ID

85037735014 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85037735014

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