期刊
BRAIN BEHAVIOR AND IMMUNITY
卷 46, 期 -, 页码 70-79出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2015.01.005
关键词
TLR2; SIGIRR; TIR8; A beta; Microglia; LTP; Hippocampus; PPAR gamma; PI3 kinase; Akt
资金
- Science Foundation Ireland
- Trinity College Postgraduate student award
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, Pam(3)CysSK(4) (Pam(3)Cys(4)), is enhanced in glial cells from SIGIRR(-/-) animals. Consistent with the view that p-amyloid peptide (A beta) signals through activation of TLR2, the data also show that A beta-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 A beta 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 (alpha TLR2) on the A beta-induced inflammatory responses and demonstrate that it prevented the expression and release of the pro-inflammatory cytokines TNF alpha and IL-6 from microglia. In addition, application of alpha TLR2 alleviated the A beta-mediated impairment in long-term potentiation (LTP) of hippocampal synaptic activity. The protective effects of alpha TLR2 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)gamma 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. (C) 2015 Elsevier Inc. All rights reserved.
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