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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:IntroductionAs the body's first line of defense against disease and infection, neutrophils must efficiently navigate to sites of inflammation; however, neutrophil dysregulation contributes to the pathogenesis of numerous diseases that leave people susceptible to infections. Many of these diseases are also associated with changes to the protein composition of the extracellular matrix. While it is known that neutrophils and endothelial cells, which play a key role in neutrophil activation, are sensitive to the mechanical and structural properties of the extracellular matrix, our understanding of how protein composition in the matrix affects the neutrophil response to infection is incomplete.MethodsTo investigate the effects of extracellular matrix composition on the neutrophil response to infection, we used an infection-on-a-chip microfluidic device that replicates a portion of a blood vessel endothelium surrounded by a model extracellular matrix. Model blood vessels were fabricated by seeding human umbilical vein endothelial cells on 2, 4, or 6 mg/mL type I collagen hydrogels. Primary human neutrophils were loaded into the endothelial lumens and stimulated by adding the bacterial pathogen Pseudomonas aeruginosa to the surrounding matrix.ResultsCollagen concentration did not affect the cell density or barrier function of the endothelial lumens. Upon infectious challenge, we found greater neutrophil extravasation into the 4 mg/mL collagen gels compared to the 6 mg/mL collagen gels. We further found that extravasated neutrophils had the highest migration speed and distance in 2mg/mL gels and that these values decreased with increasing collagen concentration. However, these phenomena were not observed in the absence of an endothelial lumen. Lastly, no differences in the percent of extravasated neutrophils producing reactive oxygen species were observed across the various collagen concentrations.DiscussionOur study suggests that neutrophil extravasation and migration in response to an infectious challenge are regulated by collagen concentration in an endothelial cell-dependent manner. The results demonstrate how the mechanical and structural aspects of the tissue microenvironment affect the neutrophil response to infection. Additionally, these findings underscore the importance of developing and using microphysiological systems for studying the regulatory factors that govern the neutrophil response.

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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