title: Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke.
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.
  
  
  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.
authors.affiliation: Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Sieber
authors.forename: Nadine
authors.initials: N
authors.lastname: Jaenisch
authors.forename: Martin
authors.initials: M
authors.lastname: Brehm
authors.forename: Madlen
authors.initials: M
authors.lastname: Guenther
authors.forename: Bettina
authors.initials: B
authors.lastname: Linnartz-Gerlach
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
authors.forename: Otto W
authors.initials: OW
authors.lastname: Witte
authors.forename: Christiane
authors.initials: C
authors.lastname: Frahm
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006706:Homeostasis; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D020768:Middle Cerebral Artery / Q000473:pathology; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism; D010587:Phagocytosis; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology*; D015424:Reperfusion; D020521:Stroke / Q000378:metabolism* / Q000473:pathology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse