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.
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The RNA-seq data have been deposited in the European Nucleotide Archive (ENA) under dataset identifier PRJEB40745. The mass spectrometry proteomic data have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository under the dataset identifier PXD018390 (reviewer token: Username: email@example.com Password:2MzhUnon). The CUT&Tag data will be made available upon request and will be publicly available after publication.
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We thank Lisa Reid, Marina Patsis, Manuela Hancock, Rhiannan Crawley, Rebekah Meeny, Tania Camilleri, and the institute flow cytometry facility for excellent technical assistance. We acknowledge the Wurundjeri people of the Kulin nation as the traditional owners and guardians of the land on which most of the work was performed. This work was supported by National Health and Medical Research Council of Australia (NHMRC) grants (1037321, 1105209, 1143976, 1150425, 1080321, 1196335, 5575500, 1054925, and 1048278), an NHMRC Independent Research Institutes Infrastructure Support Scheme grant (361646) and a Victorian State Government Operational Infrastructure Support grant. JB was supported by the Stafford Fox Medical Research Foundation.
The authors declare no competing interests.
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Zhang, S., Rautela, J., Bediaga, N.G. et al. CIS controls the functional polarization of GM-CSF-derived macrophages. Cell Mol Immunol 20, 65–79 (2023). https://doi.org/10.1038/s41423-022-00957-z