학술논문
CIS controls the functional polarization of GM-CSF-derived macrophages
Document Type
Original Paper
Author
Zhang, Shengbo; Rautela, Jai; Bediaga, Naiara G.; Kolesnik, Tatiana B.; You, Yue; Nie, Junli; Dagley, Laura F.; Bedo, Justin; Wang, Hanqing; Sun, Li; Sutherland, Robyn; Surgenor, Elliot; Iannarella, Nadia; Allan, Rhys; Souza-Fonseca-Guimaraes, Fernando; Xie, Yi; Wang, Qike; Zhang, Yuxia; Xu, Yuekang; Nutt, Stephen L.; Lew, Andrew M.; Huntington, Nicholas D.; Nicholson, Sandra E.; Chopin, Michaël; Zhan, Yifan
Source
Cellular & Molecular Immunology. 20(1):65-79
Subject
Language
English
ISSN
2042-0226
Abstract
The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation.