Monocyte chemotactic protein-induced protein 1 controls allergic airway inflammation by suppressing IL-5-producing T_H2 cells through the Notch/Gata3 pathway.

Abstract

Asthmatic and allergic inflammation is mediated by T_H2 cytokines (IL-4, IL-5, and IL-13). Although we have learned much about how T_H2 cells are differentiated, the T_H2 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 T_H2 cell differentiation and T_H2-mediated inflammation. The functions of Zc3h12a^-/- CD4 T cells were evaluated by checking the expression of T_H2 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 T_H2 inflammation. Zc3h12a^-/- mice have spontaneous severe lung inflammation, with an increase in mainly IL-5- and IL-13-producing but not IL-4-producing T_H2 cells in the lung. Mechanistically, differentiation of IL-5-producing Zc3h12a^-/- T_H2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in Zc3h12a^-/- T_H2 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 T_H2-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 T_H2 cells through the Notch/Gata3 pathway. MCPIP1 represents a new and promising target for the treatment of asthma and other T_H2-mediated diseases.