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Chronic exposure to TGF?1 regulates myeloid cell inflammatory response in an IRF7-dependent manner.

ABSTRACT: 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-M?) 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-?1 (TGF?1) 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 TGF?1 pathway. RNAi-mediated perturbation of Irf7 inhibited the M1-to-M2 switch, while IFN?1 (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.

SUBMITTER: Cohen M

PROVIDER: S-EPMC4282639 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner.

Cohen Merav M Matcovitch Orit O David Eyal E Barnett-Itzhaki Zohar Z Keren-Shaul Hadas H Blecher-Gonen Ronnie R Jaitin Diego Adhemar DA Sica Antonio A Amit Ido I Schwartz Michal M

The EMBO journal 20141110 24

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 ...[more]

PMID: 25385836

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Project description:The tumor-cell microenvironment is recognized as a dynamic place where critical cell interactions occur and play an important role in altering tumorigenesis. While many studies have investigated the effects of cellular cross-talk within distinct tumor microenvironments, these interactions have yet to be fully examined in bone. It is well-established that many common cancers metastasize to bone, resulting in the development of tumor-induced bone disease (TIBD), a multi-facetted illness that is driven by complex cell interactions within the bone marrow. Our group has previously published that myeloid progenitor cells expand in the presence of tumors in bone, aligning with the notion that myeloid cells can act as tumor promotors. Several groups, including ours, have established that transforming growth factor ? (TGF-?), an abundant growth factor in bone, can regulate both TIBD and myeloid expansion. TGF-? inhibitors have been shown to increase bone volume, decrease bone destruction, and reduce but not eliminate tumor. Therefore, we hypothesize that inhibiting TGF-? will reduce myeloid expansion leading to a reduction of tumor burden in bone and osteoclast-mediated bone loss, causing to an overall reduction in TIBD. To address this hypothesis, two different mouse models of breast cancer bone colonization were pre-treated with the TGF-? neutralizing antibody, 1D11, prior to tumor inoculation (athymic: MDA-MB-231, BALB/c: 4T1) and continuously treated until sacrifice. Additionally, a genetically modified mouse model with a myeloid specific deletion of transforming growth factor beta receptor II (TGF-?RII) (TGF-?RIIMyeKO) was utilized in our studies. Systemic inhibition of TGF-? lead to fewer osteolytic lesions, and reduced tumor burden in bone as expected from previous studies. Additionally, early TGF-? inhibition affected expansion of distinct myeloid populations and shifted the cytokine profile of pro-tumorigenic factors in bone, 4T1 tumor cells, and bone-marrow derived macrophages. Similar observations were seen in tumor-bearing TGF-?RIIMyeKO mice, where these mice contained fewer bone lesions and significantly less tumor burden in bone, suggesting that TGF-? inhibition regulates myeloid expansion leading to a significant reduction in TIBD.

Dataset Information

Chronic exposure to TGF?1 regulates myeloid cell inflammatory response in an IRF7-dependent manner.

Publications

Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner.

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