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Macrophage-Derived Angiopoietin-Like Protein 2 Exacerbates Brain Damage by Accelerating Acute Inflammation after
Toshihiro Amadatsu1,2, Jun Morinaga1, Takayuki Kawano2
1Department of Molecular Genetics, Graduate school of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
Abstract:
Ischemic stroke is a leading cause of death and disability worldwide. Several reports suggest that acute inflammation after ischemia-reperfusion exacerbates brain damage; however, molecular mechanisms underlying this effect remain unclear. Here, we report that MAC-3-positive immune cells, including infiltrating bone marrow-derived macrophages and activated microglia, express abundant angiopoietin-like protein (ANGPTL) 2 in ischemic mouse brain in a transient middle cerebral artery occlusion (MCAO) model. Both neurological deficits and infarct volume decreased in transient MCAO model mice established in Angptl2 knockout (KO) relative to wild-type mice. Acute brain inflammation after ischemia-reperfusion, as estimated by expression levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor alpha (TNF)-α, was significantly suppressed in Angptl2 KO compared to control mice. Moreover, analysis employing bone marrow chimeric models using Angptl2 KO and wild-type mice revealed that infiltrated bone marrow-derived macrophages secreting ANGPTL2 significantly contribute to acute brain injury seen after ischemia-reperfusion. These studies demonstrate that infiltrating bone marrow-derived macrophages promote inflammation and injury in affected brain areas after ischemia-reperfusion, likely via ANGPTL2 secretion in the acute phase of ischemic stroke.
Insights
Angiopoietin-like protein 2 (ANGPTL2), secreted by infiltrating macrophages, exacerbates brain damage after ischemic stroke. Reducing ANGPTL2 levels in knockout mice significantly suppressed inflammation and brain injury, highlighting its role in stroke pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Ischemic stroke is a major global health concern, leading to significant mortality and disability.
- Acute inflammation post-ischemia-reperfusion is known to worsen brain damage, but the underlying molecular mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of angiopoietin-like protein 2 (ANGPTL2) in acute brain inflammation and injury following ischemic stroke.
- To elucidate the cellular sources and mechanisms by which ANGPTL2 contributes to brain damage in a mouse model of ischemic stroke.
Main Methods:
- Utilized a transient middle cerebral artery occlusion (MCAO) model in wild-type and Angptl2 knockout (KO) mice.
- Assessed neurological deficits and infarct volume.
- Measured expression levels of pro-inflammatory cytokines (IL-1β, TNF-α).
- Employed bone marrow chimeric models to distinguish the contribution of infiltrated macrophages.
Main Results:
- Angiopoietin-like protein 2 (ANGPTL2) was highly expressed by MAC-3-positive immune cells (macrophages, microglia) in the ischemic mouse brain.
- Angptl2 KO mice exhibited reduced neurological deficits and infarct volume compared to wild-type mice.
- Acute brain inflammation, indicated by lower pro-inflammatory cytokine levels, was suppressed in Angptl2 KO mice.
- Bone marrow chimeric studies demonstrated that infiltrated bone marrow-derived macrophages secreting ANGPTL2 significantly contribute to ischemia-reperfusion injury.
Conclusions:
- Infiltrating bone marrow-derived macrophages promote inflammation and brain injury after ischemic stroke, primarily through the secretion of ANGPTL2 in the acute phase.
- ANGPTL2 is a key mediator of post-ischemic inflammation and brain damage, representing a potential therapeutic target for ischemic stroke.
