Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner
Open accessAbstract
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.
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INF and TGF-β1/Smad signaling are co-regulated in activated microglia, and Smad2/3 directly regulates expression of several homeostatic markers including P2ry12.
“Consistent with this, INF and TGF-β1/Smad signaling are co-regulated in activated microglia32, and Smad2/3 is known to directly regulate the expression of several homeostatic markers including P2ry1233.”
From A comparative evaluation of the strengths and potential caveats of the microglial inducible CreER mouse models (2024) · cites this paper as [32]
The Discussion (page unavailable) links TGF-β/Smad3 signaling to IRF7 activity and IFN-β expression, while the paper reports that prolonged TGF-β1 exposure suppresses IRF7 in microglia. This supports an interaction between the pathways, but does not establish that IFN and TGF-β1/Smad signaling are co-regulated in activated microglia. The Smad2/3–P2ry12 statement carries a different citation and is not assessed here. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe cause of microglial priming is unclear and likely results from multiple factors, including loss of inhibitory ligand-receptor communication with aging neurons, interactions with age-related misfolded proteins such as Aβ, age-related exposure to increasing transforming growth factor-β, age-related alterations in production of IL-4 and CCL11 in the choroid plexus, and unique microenvironmental 3
“The cause of microglial priming is unclear and likely results from multiple factors, including but not limited to (1) a loss of inhibitory ligand–receptor communication with aging neurons (94), (2) interactions with age-related misfolded proteins such as Aβ which promote pro-inflammatory cytokine production (95), (3) age-related exposure to increasing transforming growth factor-β which could”
From The Inflammatory Continuum of Traumatic Brain Injury and Alzheimer’s Disease (2018) · cites this paper as [96]
The Results section on the M1-to-M2 phenotype switch reports that prolonged TGFβ1 exposure impaired microglia’s ability to adopt an anti-inflammatory phenotype. The Discussion links this effect to chronic exposure in the adult CNS, but our copy does not show that TGFβ exposure increases with age or establish it as a cause of age-related microglial priming. Page numbers were not available in the indexed passages. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTgfbr2 and Csf1r play an essential signaling role in microglia development, with absence or inhibition causing marked reduction or complete absence of microglia.
“Tgfbr2 and Csf1r have also been demonstrated to play an essential signaling role in microglia development, where the absence of these genes or inhibition of their signaling shows marked reduction or complete absence of microglia”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Cohen et al., 2014
The Results section on long TGFβ1 exposure reports Tgfbr2 expression in adult microglia, but does not test its role in microglial development. The Discussion addresses inflammatory phenotype switching, not developmental loss of microglia. Searches for Csf1r, gene absence, inhibition, and microglial depletion found no passage supporting the claimed reduction or absence of microglia. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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- Authors
- Cohen, M., Matcovitch, O., David, E., Barnett‐Itzhaki, Z., Keren‐Shaul, H., Blecher‐Gonen, R., Jaitin, D. A., Sica, A., Amit, I., & Schwartz, M.
- Affiliations
- Weizmann Institute of Science (IL)
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- Corresponding author
- Amit, Ido
- Schwartz, Michal
- ORCID
- Venue
- The EMBO Journal
- Published
- 2014-11-10
- Volume
- 33
- Issue
- 24
- Pages
- 2906-2921
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4282639
- OpenAlex
- W2096225770
- Cited by
- 142
- References
- 15
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 14 · 2023: 8 · 2022: 16 · 2021: 9 · 2020: 10 · 2019: 8 · 2018: 12 · 2017: 17 · 2016: 12 · 2015: 8 · 2014: 1
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Research Council (232835, 309788)
- EU Seventh Framework Program HEALTH‐2011 (279017)
- Israeli Science Foundation (1782/11)
- Human Frontiers Science Program, Career Development Award
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TGF-β1, IRF7, myeloid cells, microglia, monocyte-derived macrophages, anti-inflammatory phenotype, interferon-beta, spinal cord injury, tissue microenvironment, chronic inflammation, neuroinflammation
- MeSH terms
- Animals, Gene Expression Regulation, Mice, Inbred C57BL, Gene Expression Profiling, Myeloid Cells, Chromatin Immunoprecipitation, Interferon Regulatory Factor-7, Transforming Growth Factor beta1, High-Throughput Nucleotide Sequencing
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