CIS controls the functional polarization of GM-CSF-derived macrophages
- Author(s)
- Zhang, S; Rautela, J; Bediaga, NG; Kolesnik, TB; You, Y; Nie, J; Dagley, LF; 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, SL; Lew, AM; Huntington, ND; Nicholson, SE; Chopin, M; Zhan, Y;
- Journal Title
- Cellular & Molecular Immunology
- Publication Type
- epub ahead of print
- 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.
- Publisher
- NPG
- Keywords
- Cis; Gm-csf; M1; M2; Macrophage
- Research Division(s)
- Immunology; Advanced Technology And Biology; Bioinformatics; Blood Cells And Blood Cancer; Cancer Biology And Stem Cells; Epigenetics And Development; Inflammation
- PubMed ID
- 36471114
- Publisher's Version
- https://doi.org/10.1038/s41423-022-00957-z
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-12-13 03:13:15
Last Modified: 2022-12-14 01:18:04