Type

Journal Article

Authors

Marina A Lynch
Dónal G Carney
Derek A Costello

Subjects

Biochemistry

Topics
interleukin 1 inflammatory response amyloid peptide a up regulation toll like receptor 4 long term potentiation ltp peroxisome proliferator activated receptor antibody response

α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR. (2014)

Abstract The immunoregulatory function of single-Ig-interleukin-1 related receptor (SIGIRR) is derived from its ability to constrain the inflammatory consequences of interleukin (IL)-1R and toll-like receptor (TLR)4 activation. This role extends to the brain, where SIGIRR deficiency increases the synaptic and cognitive dysfunction associated with IL-1R- and TLR4-mediated signalling. The current study set out to investigate the interaction between SIGIRR and TLR2 in brain tissue and the data demonstrate that the response to the TLR2 agonist, Pam3CysSK4 (Pam3Cys4), is enhanced in glial cells from SIGIRR(-/-) animals. Consistent with the view that β-amyloid peptide (Aβ) signals through activation of TLR2, the data also show that Aβ-induced changes are exaggerated in glia from SIGIRR(-/-) animals. We report that microglia, rather than astrocytes, are the primary glial cell expressing both TLR2 and SIGIRR. While Aβ increased TLR2 expression, it decreased SIGIRR expression in microglia. This was mimicked by direct activation of TLR2 with Pam3Cys4. We investigated the effect of an anti-TLR2 antibody (αTLR2) on the Aβ-induced inflammatory responses and demonstrate that it prevented the expression and release of the pro-inflammatory cytokines TNFα and IL-6 from microglia. In addition, application of αTLR2 alleviated the Aβ-mediated impairment in long-term potentiation (LTP) of hippocampal synaptic activity. The protective effects of αTLR2 were accompanied by an up-regulation in SIGIRR expression. We propose that a mechanism involving activation of PI3 kinase/Akt and the transcription factor peroxisome proliferator-activated receptor (PPAR)γ may facilitate this increase in SIGIRR. These findings highlight a novel role of SIGIRR as a negative regulator of TLR2-mediated inflammation in the brain.
Collections Ireland -> Trinity College Dublin -> PubMed

Full list of authors on original publication

Marina A Lynch, Dónal G Carney, Derek A Costello

Experts in our system

1
Marina Annetta Lynch
Trinity College Dublin
Total Publications: 80