TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage
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
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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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 6

An increase in TGF-β1 plasma levels from 6 to 72 hours after ICH is independently associated with better patient outcomes at 90 days.

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An increase in TGF-β1 plasma levels from 6 to 72 hours after ICH is inde...
Plasma TGF-β1 concentrations were measured from controls and ICH patients at 6 ± 6 and 72 ± 6 hours after onset of ICH. (A) Each control patient’s TGF-β1 plasma level is depicted as a gray dot, with the line indicating the median. Each individual patient’s TGF-β1 plasma level is depicted as a dot, with a line connecting each patient’s 6- and 72-hour data. Those who had a decrease in TGF-β1 plasma are depicted in red. (B) Distribution of patient outcomes on the modified Rankin scale by TGF-β1 response. n = 22 controls and 22 ICH patients.