Abstract
BackgroundTriggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery. The role of TREM2 following stroke is currently unclear.Methods and ResultsAs an experimental stroke model, the middle cerebral artery of mice was occluded for 30 minutes with a range of reperfusion times (duration of reperfusion: 6 h/12 h/24 h/2 d/7 d/28 d). Quantitative PCR (qPCR) revealed a greatly increased transcription of TREM2 after stroke. We subsequently analyzed the expression of pro-inflammatory cytokines, chemokines and their receptors in TREM2-knockout (TREM2-KO) mice via qPCR. Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via qPCR and immunohistochemistry. Functional consequences of TREM2 knockout were assessed by infarct volumetry. The acute inflammatory response (12 h reperfusion) was very similar between TREM2-KO mice and their littermate controls. However, in the sub-acute phase (7 d reperfusion) following stroke, TREM2-KO mice showed a decreased transcription of pro-inflammatory cytokines TNFα, IL-1α and IL-1β, associated with a reduced microglial activity (CD68, Iba1). Furthermore, TREM2-KO mice showed a reduced transcription of chemokines CCL2 (MCP1), CCL3 (MIP1α) and the chemokine receptor CX3CR1, followed by a diminished invasion of CD3-positive T-cells. No effect on the lesion size was observed.ConclusionsAlthough we initially expected an exaggerated pro-inflammatory response following ablation of TREM2, our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice. We therefore conclude that TREM2 appears to sustain a distinct inflammatory response after stroke.
Highlights
Cerebral ischemia triggers inflammatory processes which start within hours and last up to weeks [1,2,3]
Conclusions: we initially expected an exaggerated pro-inflammatory response following ablation of Triggering receptor expressed on myeloid cells-2 (TREM2), our data support a contradictory scenario that the sub-acute inflammatory reaction after stroke is attenuated in TREM2-KO mice
Microglial activation (CD68, Iba1) and CD3-positive T-cell invasion were analyzed via Quantitative PCR (qPCR) and immunohistochemistry
Summary
Cerebral ischemia triggers inflammatory processes which start within hours and last up to weeks [1,2,3]. Resident cells of the innate immune system, predominantly microglia, secrete inflammatory mediators such as cytokines and chemokines, which in turn activate microglial cells and recruit peripheral immune cells [4]. The inflammatory response after stroke represents an opportunity to influence disease progression and post-stroke recovery. Post-ischemic phagocytosis of cell debris is crucial for resolving inflammation and reconstitution of tissue homeostasis. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial receptor which delivers intracellular signals via the adaptor protein DAP12 [7,8]. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial surface receptor involved in phagocytosis. Clearance of apoptotic debris after stroke represents an important mechanism to re-attain tissue homeostasis and thereby ensure functional recovery.
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