α-TLR2 antibody attenuates the Aß-mediated inflammatory response in microglia through enhanced expression of SIGIRR.

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 ß-amyloid peptide (Aß) signals through activation of TLR2, the data also show that Aß-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 Aß 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 Aß-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 Aß-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.

SIGIRR modulates the inflammatory response in the brain.

One of the more recently described members of the interleukin-1 (IL-1) receptor family, single-Ig-interleukin-1 related receptor (SIGIRR), has been identified as a negative regulator of inflammation in several tissues. It modulates the responses triggered by stimulation of Toll-like receptor (TLR) 4 and IL-1 in several peripheral cell types, possibly in an NFkappaB-dependent manner. Consistently, responses to lipopolysaccharide (LPS) are exaggerated in SIGIRR-deficient mice and the symptoms of experimental inflammatory conditions are more profound in these animals. Here, we set out to establish whether the absence of SIGIRR was associated with inflammatory changes in the brain and report that, LPS-induced a greater effect on CD40 and ICAM mRNA in mixed glia prepared from SIGIRR(-/-), compared with wildtype mice. This was associated with parallel changes in TNFalpha and IL-6 at mRNA and protein levels, an effect which was observed in purified microglia but not astrocytes. Similarly, LPS exerted a more profound effect on microglial activation and cytokine production in hippocampal tissue prepared from SIGIRR(-/-), compared with wildtype mice. The effect of LPS on exploratory behaviour was also accentuated in SIGIRR(-/-) mice. The evidence suggests that these changes are a likely consequence of increased hippocampal expression of CD14 and TLR4, and NFkappaB activation in SIGIRR(-/-) mice.