| Autor: |
Shengbo Zhang, Jai Rautela, Naiara G Bediaga, Tatiana B Kolesnik, Yue You, Laura F Dagley, Justin Bedo, Hanqing Wang, Li Sun, Robyn Sutherland, Elliot Surgenor, Nadia Iannarella, Rhys Allan, Fernando Souza-Fonseca-Guimaraes, Yi Xie, Qike Wang, Yuxia Zhang, Yuekang Xu, Stephen L Nutt, Andrew M Lew, Nicholas D Huntington, Sandra E Nicholson, Michaël Chopin, Yifan Zhan |
| Rok vydání: |
2022 |
| Popis: |
The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages (MØs) with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here we show that GM-CSF induced MØs polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like MØs expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in MØ differentiation and uncovering its role in controlling allergic inflammation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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