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

J Clin Invest. 2017 Jan 3;127(1):280-292. doi: 10.1172/JCI88647. Epub 2016 Nov 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Injuries / blood*
  • Brain Injuries / etiology
  • Cerebral Hemorrhage / blood*
  • Cerebral Hemorrhage / genetics
  • Cerebral Hemorrhage / pathology
  • Gene Expression Regulation
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism*
  • Microglia / pathology
  • Recovery of Function*
  • Signal Transduction*
  • Transforming Growth Factor beta1 / blood*
  • Transforming Growth Factor beta1 / genetics

Substances

  • Interleukin-6
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • interleukin-6, mouse