Tissue microenvironment influences the function of resident and infiltrating myeloid-derived cells. In the central nervous system (CNS), resident microglia and freshly recruited infiltrating monocyte-derived macrophages (mo-MΦ) display distinct activities under pathological conditions, yet little is known about the microenvironment-derived molecular mechanism that regulates these differences. Here, we demonstrate that long exposure to transforming growth factor-β1 (TGFβ1) impaired the ability of myeloid cells to acquire a resolving anti-inflammatory phenotype. Using genome-wide expression analysis and chromatin immunoprecipitation followed by next-generation sequencing, we show that the capacity to undergo pro- to anti-inflammatory (M1-to-M2) phenotype switch is controlled by the transcription factor interferon regulatory factor 7 (IRF7) that is down-regulated by the TGFβ1 pathway. RNAi-mediated perturbation of Irf7 inhibited the M1-to-M2 switch, while IFNβ1 (an IRF7 pathway activator) restored it. In vivo induction of Irf7 expression in microglia, following spinal cord injury, reduced their pro-inflammatory activity. These results highlight the key role of tissue-specific environmental factors in determining the fate of resident myeloid-derived cells under both physiological and pathological conditions. Synopsis Chronic exposure to the abundant CNS cytokine, TGFβ1, impairs the ability of myeloid cells, specifically microglia, to acquire an inflammation-resolving, anti-inflammatory (M2), phenotype under pathological conditions. The transcription factor IRF7 is a key regulator of the M1-to-M2 phenotype switch and is down-regulated by the TGFβ1 signaling pathway. Induction of IRF7 expression by IFN-β1 under pathological conditions reduces microglial pro-inflammatory response following injury. Extended exposure to TGFβ1 prevents myeloid cells to switch phenotype under inflammatory conditions. IRF7 regulates the M1-to-M2 phenotype switch in myeloid cells through down-regulation of pro-inflammatory genes. The prevalent cytokine in the adult CNS milieu, TGFβ1, suppresses IRF7 expression. IRF7 induction restores the ability of microglia to acquire an M2-like phenotype under inflammatory conditions. TGFβ1 regulates the ability of microglia to acquire an inflammation resolving phenotype under pathological conditions by down-regulating the expression of the transcription factor IRF7.
- central nervous system
- myeloid cells
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)