Publication date: Available online 27 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Hui Peng, Huan Ning, Qinghong Wang, Wenbao Lu, Yingzi Chang, Tony T. Wang, Jinping Lai, Pappachan E. Kolattukudy, Rong Hou, Daniel F. Hoft, Mark S. Dykewicz, Jianguo Liu
BackgroundAsthmatic and allergic inflammation is mediated by Th2 cytokines (IL-4, IL-5 and IL-13). Though we have learned much about how Th2 cells are differentiated, the Th2 checkpoint mechanisms remain elusive.ObjectivesIn this study, we investigate how monocyte chemotactic protein induced protein-1 (MCPIP1, encoded by zc3h12a gene) regulates IL-5-producing Th2 cell differentiation and Th2-mediated inflammation.MethodsThe 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 WT recipient mice, challenged with OVA or HDM, and accessed for Th2 inflammation.ResultsZc3h12a-/- mice spontaneously develop severe lung inflammation, with an increase mainly in IL-5- and IL-13-producing but not IL-4-producing Th2 cells in the lung. Mechanistically, the 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 via 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.ConclusionsOur study reveals that MCPIP1 regulates the development and functions of IL-5-producing Th2 cells through Notch/Gata3 pathway. MCPIP1 represents a new promising target for the treatments of asthma and other Th2-mediated diseases.
Graphical abstract
http://ift.tt/2hi2sl3
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου