Zhang, S.Rautela, J.Bediaga, N.G.Kolesnik, T.B.You, Y.Nie, J.Dagley, L.F.Bedo, J.Wang, H.Sun, L.Sutherland, R.Surgenor, E.Iannarella, N.Allan, R.Souza-Fonseca-Guimaraes, F.Xie, Y.Wang, Q.Zhang, Y.Xu, Y.Nutt, S.L.et al.2023-01-252023-01-252022Cellular and Molecular Immunology, 2022; 20(1):65-791672-76812042-0226https://hdl.handle.net/2440/137317The 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.en© 2022, The Author(s), under exclusive licence to CSI and USTCMonocytesMacrophagesGranulocyte-Macrophage Colony-Stimulating FactorCytokinesCell DifferentiationInterferon Regulatory FactorsMonocytesMacrophagesGranulocyte-Macrophage Colony-Stimulating FactorCytokinesCell DifferentiationInterferon Regulatory FactorsJournal article10.1038/s41423-022-00957-z2023-01-25629664