# Microglia/macrophage polarization after intracerebral hemorrhage

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $450,874

## Abstract

PROJECT SUMMARY:
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/MΦ) shift activity states after ICH to remove
toxic blood and may protect the brain. However, over-activated M/MΦ cause secondary brain damage by
releasing cytotoxic substances. These opposing effects may result from distinct M/MΦ 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/MΦ 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/MΦ
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/MΦ 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/MΦ polarization by IL-10 improves histologic and functional outcomes after ICH in vivo
(Aim 2); and whether IL-10 induction of M/MΦ 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/MΦ polarization after
ICH and the cellular and molecular mechanisms by which IL-10 signaling–induced M/MΦ M2 polarization
reduces ICH injury. Based on multidisciplinary approaches, our findings will potentially lead to a new therap...

## Key facts

- **NIH application ID:** 10168662
- **Project number:** 5R01NS102583-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** RAYMOND Charles KOEHLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,874
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168662

## Citation

> US National Institutes of Health, RePORTER application 10168662, Microglia/macrophage polarization after intracerebral hemorrhage (5R01NS102583-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10168662. Licensed CC0.

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