Post-ischemic inflammation in the brain

Takashi Shichita, Ryota Sakaguchi, Mayu Suzuki, Akihiko Yoshimura, Takashi Shichita, Ryota Sakaguchi, Mayu Suzuki, Akihiko Yoshimura

Abstract

Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In this review, we focus on the post-ischemic inflammation triggered by infiltrating immune cells, macrophages, and T lymphocytes. Brain ischemia is a sterile organ, but injury-induced inflammation is mostly dependent on Toll-like receptor (TLR) 2 and TLR4. Some endogenous TLR ligands, high mobility group box 1 (HMGB1) and peroxiredoxin family proteins, in particular, are implicated in the activation and inflammatory cytokine expression in infiltrating macrophages. Following macrophage activation, T lymphocytes infiltrate the ischemic brain and regulate the delayed phase inflammation. IL-17-producing γδT lymphocytes induced by IL-23 from macrophages promote ischemic brain injury, whereas regulatory T lymphocytes suppress the function of inflammatory mediators. A deeper understanding of the inflammatory mechanisms of infiltrating immune cells may lead to the development of novel neuroprotective therapies.

Keywords: DAMPs; T cells; brain; cytokine; inflammation; ischemia; macrophages; stroke.

Figures

Figure 1
Figure 1
Post-ischemic inflammation in the brain. Within 24 h after ischemic stroke onset, various inflammatory mediators are expressed in ischemic brain tissue. ICAM-1 promotes leukocytes infiltration. Cytokines activate infiltrating leukocytes and directly induce ischemic injury in brain cells. Matrix metalloproteinases (MMPs) alter the permeability of epithelial cells and are implicated in BBB breakdown. Endogenous TLR ligands (DAMPs) are released from necrotic brain cells and activate infiltrating immune cells. These inflammatory mediators trigger post-ischemic inflammation by infiltrating leukocytes. There are currently few effective therapies for this phase of leukocyte infiltration.
Figure 2
Figure 2
Two opposing functions of Prx, one inside, and one outside, brain cells. Ischemic stress increases Prx expression within brain cells, which contributes to their survival by catabolizing reactive oxygen species (ROS). When ischemic phenomena finally result in necrosis, the Prx released from necrotic brain cells into the extracellular compartment then functions as a strong TLR2 and TLR4 stimulator (DAMP) for the infiltrating macrophages in ischemic brain tissue.
Figure 3
Figure 3
Post-ischemic inflammation triggered by DAMPs and infiltrating immune cells. At the hyperacute phase of brain ischemia (within 6 h after stroke onset), HMGB1 is released from brain cells and induces BBB breakdown. Following this, blood cells begin to infiltrate into ischemic brain tissue via disrupted vessels during the acute phase of ischemia (12–24 h after stroke onset). Prx is extracellularly released from necrotic brain cells and activates infiltrating macrophages via TLR2 and TLR4. Activated macrophages produce inflammatory cytokines (IL-23, IL-1β, TNF-α, etc.) which promote ischemic brain injury. At the delayed phase of brain ischemia (more than 24 h after stroke onset), IL-23 induces IL-17 production from γδT lymphocytes, which further enhances ischemic damage. Thus, HMGB1 is a hyperacute DAMP, while Prx is secondarily active in post-ischemic inflammation, during the acute phase.
Figure 4
Figure 4
Schematic model of IL-23/IL-17 inflammatory pathway in ischemic brain tissue. Infiltrating macrophages produce IL-23 and IL-12, which induce IL-17-producing γδT lymphocytes and IFN-γ-producing helper T lymphocytes (Th1), respectively. IL-17 from γδT lymphocytes acts on macrophages and brain cells directly, and promotes the expression of inflammatory mediators that enhance apoptotic neuronal cell death and BBB breakdown.
Figure 5
Figure 5
Strategy for developing neuroprotective therapy by suppressing neurotoxic inflammatory response. The targeting of specific inflammatory mediators from macrophages and T lymphocytes can attenuate neurotoxic inflammatory reactions.

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