TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage
Roslyn A. Taylor, … , J. Christopher Love, Lauren H. Sansing
Roslyn A. Taylor, … , J. Christopher Love, Lauren H. Sansing
Published November 28, 2016
Citation Information: J Clin Invest. 2017;127(1):280-292. https://doi.org/10.1172/JCI88647.
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Research Article Inflammation Neuroscience

TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a devastating form of stroke that results from the rupture of a blood vessel in the brain, leading to a mass of blood within the brain parenchyma. The injury causes a rapid inflammatory reaction that includes activation of the tissue-resident microglia and recruitment of blood-derived macrophages and other leukocytes. In this work, we investigated the specific responses of microglia following ICH with the aim of identifying pathways that may aid in recovery after brain injury. We used longitudinal transcriptional profiling of microglia in a murine model to determine the phenotype of microglia during the acute and resolution phases of ICH in vivo and found increases in TGF-β1 pathway activation during the resolution phase. We then confirmed that TGF-β1 treatment modulated inflammatory profiles of microglia in vitro. Moreover, TGF-β1 treatment following ICH decreased microglial Il6 gene expression in vivo and improved functional outcomes in the murine model. Finally, we observed that patients with early increases in plasma TGF-β1 concentrations had better outcomes 90 days after ICH, confirming the role of TGF-β1 in functional recovery from ICH. Taken together, our data show that TGF-β1 modulates microglia-mediated neuroinflammation after ICH and promotes functional recovery, suggesting that TGF-β1 may be a therapeutic target for acute brain injury.

Authors

Roslyn A. Taylor, Che-Feng Chang, Brittany A. Goods, Matthew D. Hammond, Brian Mac Grory, Youxi Ai, Arthur F. Steinschneider, Stephen C. Renfroe, Michael H. Askenase, Louise D. McCullough, Scott E. Kasner, Michael T. Mullen, David A. Hafler, J. Christopher Love, Lauren H. Sansing

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Figure 2

Temporal transcriptional analysis of microglia after ICH.

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Temporal transcriptional analysis of microglia after ICH. (A) Scatter pl...
(A) Scatter plots show each sample projected on the first two principal components and are color coded according to time point. Biological replicates cluster closely at each time point. (B) Heatmap of the Z score of genes identified by PCA for each sample. Data were clustered hierarchically in GENE-E using one minus Pearson correlation and complete linkage. Data are colored according to row minimum and maximum. Time points are color coded as in A, and days 10–28 cluster most closely. Each replicate includes microglia from 3 brains, and there are 3 biological replicates per time point. (C) GO biological process enrichment analysis was performed using genes appearing in the resolution phase quadrant of the PCA. TGF-β1 pathways account for the majority of the top 15 GO functions. (D) The network diagram shows each gene identified in the resolution phase, including TGF-β1, as a node, and connections are indicated by function.