title: Toll-like receptor 2 deficiency leads to delayed exacerbation of ischemic injury.
abstract: BACKGROUND
  Using a live imaging approach, we have previously shown that microglia activation after stroke is characterized by marked and long-term induction of the Toll-like receptor (TLR) 2 biophotonic signals. However, the role of TLR2 (and potentially other TLRs) beyond the acute innate immune response and as early neuroprotection against ischemic injury is not well understood.
  
  
  METHODS
  TLR2-/- mice were subjected to transient middle cerebral artery occlusion followed by different reperfusion times. Analyses assessing microglial activation profile/innate immune response were performed using in situ hybridization, immunohistochemistry analysis, flow cytometry and inflammatory cytokine array. The effects of the TLR2 deficiency on the evolution of ischemic brain injury were analyzed using a cresyl violet staining of brain sections with appropriate lesion size estimation.
  
  
  RESULTS
  Here we report that TLR2 deficiency markedly affects post-stroke immune response resulting in delayed exacerbation of the ischemic injury. The temporal analysis of the microglia/macrophage activation profiles in TLR2-/- mice and age-matched controls revealed reduced microglia/macrophage activation after stroke, reduced capacity of resident microglia to proliferate as well as decreased levels of monocyte chemotactic protein-1 (MCP-1) and consequently lower levels of CD45(high)/CD11b(+) expressing cells as shown by flow cytometry analysis. Importantly, although acute ischemic lesions (24 to 72 h) were smaller in TLR2-/- mice, the observed alterations in innate immune response were more pronounced at later time points (at day 7) after initial stroke, which finally resulted in delayed exacerbation of ischemic lesion leading to larger chronic infarctions as compared with wild-type mice. Moreover, our results revealed that TLR2 deficiency is associated with significant decrease in the levels of neurotrophic/anti-apoptotic factor Insulin-like growth factor-1 (IGF-1), expressed by microglia in the areas both in and around ischemic lesion.
  
  
  CONCLUSIONS
  Our results clearly suggest that optimal and timely microglial activation/innate immune response is needed to limit neuronal damage after stroke.
authors.affiliation: Laboratory for Neurogenetics and Developmental Genetics, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 12, Zagreb HR-10000, Croatia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bohacek
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordeau
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lalancette-Hébert
authors.forename: Dunja
authors.initials: D
authors.lastname: Gorup
authors.forename: Yuan-Cheng
authors.initials: YC
authors.lastname: Weng
authors.forename: Srecko
authors.initials: S
authors.lastname: Gajovic
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
chemical_list: C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2