Activation of microglial Toll‐like receptor 3 promotes neuronal survival against cerebral ischemia

Abstract

Emerging experimental evidence suggests that activation of Toll-like receptor 3 (TLR3) by its agonist polyinosinic polycytidylic acid (poly-ICLC) protects neurons against cerebral ischemia, but the underlying mechanisms remain largely unknown. In the brain, TLR3 is mostly expressed in glial cells. Therefore, we assess the hypothesis that TLR3 activation in microglia is required for neuroprotection against ischemia. After transient focal cerebral ischemia, microglia/macrophages (MMs) demonstrate a significant reduction in TLR3 and its downstream cytokine interleukin 6 (IL-6). Subsequently, activation of TLR3 by poly-ICLC restored TLR3 expression and decreased infarction. To further investigate these mechanisms, we turned to a primary cell culture system. Consistent with the in vivo findings, oxygen-glucose deprivation (OGD) significantly reduced TLR3 and IL-6 mRNA expression in microglia, but poly-ICLC significantly rescued TLR3 and IL-6 expression. Importantly, conditioned media from OGD-treated microglia increased neuronal death after OGD. In contrast, the conditioned media from microglia treated with poly-ICLC after OGD significantly protected against OGD-induced neuron death. Taken together, our findings provide proof-of-concept that activation of TLR3 in microglia may promote neuron survival after ischemia.

Protective Effects of Lycium barbarum Extracts on UVB‐Induced Damage in Human Retinal Pigment Epithelial Cells Accompanied by Attenuating ROS and DNA Damage

“…Bsibsi et al's work showed that inflammation-induced TLR-3 activation triggers a neuroprotective response rather than a proinflammatory response in human astrocytes [ 59 ]. Furthermore, Jeong et al's work showed that polyinosinic poly-cytidylic acid- (poly(I:C)-) induced activation of TLR3 might favor the survival of microglia after cerebral ischemia, suggesting the neuroprotective role of TLR3 [ 60 ]. Controversially, the activation of TLR might also create a degenerative effect in neuron cells; for example, Chintala et al's work showed that poly(I:C)-induced TLR3 activation upregulated the protein level of MAPK JNK3 and promoted the degeneration of RGCs in mouse eye [ 61 ].…”

“…Similarly, Gao et al's work showed that poly(I:C)-induced TLR3 evoked an inflammatory response and cell death both in murine photoreceptor 661W cells and an in vivo model [ 62 ]. Therefore, the role of TLR in prosurvival or pro-cell death of neuron cells may depend on the types [ 55 ] of stimuli, the level [ 60 ] of stimuli, and the downstream of TLR signaling [ 58 ].…”

Neuron‐microglia interaction induced bi‐directional cytotoxicity associated with calpain activation

“…; Jeong et al . ) and conversion between different phenotypes seems now critical next step to clarify the factors that initiate or promote such changes. Thus, inhibition of microglia and T‐cell activation by calpain inhibitor as a therapeutic agent may block neuron death and axonal damage to reduce progression of the degenerative process.…”

Potential Medications or Compounds Acting on Toll-like Receptors in Cerebral Ischemia

“…An emerging proof-of-concept studies [ 133 ] provided that a TLR3 ligand, which consists of carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA (named poly-ICLC) working as an activation of TLR3 in microglia is also neuroprotective. After focal cerebral ischemia, as well as OGD, TLR3 and IL-6 were found downregulated in microglia/macrophage.…”