Microglia/macrophage polarization after intracerebral hemorrhage Spontaneous intracerebral hemorrhage (ICH) causes high mortality and morbidity, but it is understudied compared to ischemic stroke and lacks effective treatment. Greater hematoma volume and expansion are independently associated with poor patient outcomes; therefore, rapid removal of toxic blood could limit ICH- induced brain injury. Additionally, microglia and macrophages (M/M?) shift activity states after ICH to remove toxic blood and may protect the brain. However, over-activated M/M? cause secondary brain damage by releasing cytotoxic substances. These opposing effects may result from distinct M/M? subsets, which are categorized into classically activated proinflammatory (M1) and alternatively activated anti-inflammatory (M2) cells. Alternatively activated M2 macrophages exhibit increased phagocytosis of apoptotic cells, which could involve activation of the scavenger receptor CD36 and inhibition of its negative regulator, toll-like receptor (TLR) 4. Importantly, interleukin-10 (IL-10), an anti-inflammatory cytokine, represses inflammation, polarizes macrophages to an M2c subtype, and enhances phagocytosis. Patients with ICH have elevated levels of IL-10 in blood and brain tissue. However, the extent and timing of M/M? polarization and the exact role of IL-10 signaling in M2 polarization after ICH are unknown. The long-term goal of our research is to limit ICH injury and improve functional outcomes. The overall objective of this R01 is to investigate whether modulation of M/M? phenotype and function by IL-10 reduces ICH injury and improves histologic and functional outcomes. Our preliminary studies showed that IL-10 expression increases in brain slice cultures exposed to hemoglobin and in an in vivo model of ICH; that IL-10 increases microglial phagocytosis and CD36 expression in brain slice cultures; that IL-10-deficient mice have impaired hematoma resolution and altered CD36 and TLR4 expression compared to C57BL/6 wild-type mice; and that exogenous IL-10 successfully reduces hematoma volume. These findings prompt the hypothesis that polarizing M/M? to M2 phenotype by IL-10 reduces ICH injury and improves histologic and functional recovery after ICH. In three specific aims, we will determine whether M2 microglial polarization by IL-10 is responsible for phagocytosis in ex vivo brain slice cultures exposed to blood components (Aim 1); whether M2 M/M? polarization by IL-10 improves histologic and functional outcomes after ICH in vivo (Aim 2); and whether IL-10 induction of M/M? M2 polarization requires activation of CD36 and inhibition of TLR4 (Aim 3). The information gained from this study will provide us with novel insight into the M/M? polarization after ICH and the cellular and molecular mechanisms by which IL-10 signaling?induced M/M? M2 polarization reduces ICH injury. Based on multidisciplinary approaches, our findings will potentially lead to a new therapeutic strategy not only for ICH but also for other brain disorders. This novel proof-of-concept work to study modulation of M/M? polarization is a critical priority identified by the recent NINDS-SPRG.
Bleeding in the brain, or intracerebral hemorrhage (ICH), has no effective treatment and can cause death or permanent disability. Activated microglia and infiltrating macrophages (types of white blood cells) can either increase damage by secreting inflammatory factors or help the brain to recover by clearing blood debris and dead/dying cells. We will attempt to increase the protective effects of microglia and macrophages by modulating interleukin-10, an anti-inflammatory factor released by these cells, and determine the underlying molecular mechanisms by which interleukin-10, CD36, and toll-like receptor 4 act on the hemorrhagic brain.
|Lan, Xi; Han, Xiaoning; Liu, Xi et al. (2018) Inflammatory responses after intracerebral hemorrhage: From cellular function to therapeutic targets. J Cereb Blood Flow Metab :271678X18805675|
|Zhu, Wei; Gao, Yufeng; Wan, Jieru et al. (2018) Changes in motor function, cognition, and emotion-related behavior after right hemispheric intracerebral hemorrhage in various brain regions of mouse. Brain Behav Immun 69:568-581|