Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke

PLoS One. 2013;8(1):e52982. doi: 10.1371/journal.pone.0052982. Epub 2013 Jan 3.

Abstract

Background: 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. The role of TREM2 following stroke is currently unclear.

Methods and results: As 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.

Conclusions: Although 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Brain / pathology
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Homeostasis
  • Immunohistochemistry
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Male
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Middle Cerebral Artery / pathology
  • Myeloid Cells / cytology*
  • Myeloid Cells / metabolism
  • Phagocytosis
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / physiology*
  • Reperfusion
  • Stroke / metabolism*
  • Stroke / pathology*

Substances

  • Chemokines
  • Cytokines
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse

Grant support

This project was supported by the European Union (STREP, FP6, ‘Age-dependent inflammatory response after stroke’ – ARGES [LSHB-CT-2006-018936]) and is part of the research program of the Jena centre for systems biology of ageing – Jenage (BMBF 0315581). The Neural Regeneration Group at the University Bonn LIFE & BRAIN Center is supported by the Hertie-Foundation and the Deutsche Forschungsgemeinschaft (KFO177, SFB704, FOR1336). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.