TLR3 ligand Poly IC Attenuates Reactive Astrogliosis and Improves Recovery of Rats after Focal Cerebral Ischemia

Abstract

SUMMARY Aims Brain ischemia activates astrocytes in a process known as astrogliosis. Although this process has beneficial effects, excessive astrogliosis can impair neuronal recovery. Polyinosinic–polycytidylic acid (Poly IC) has shown neuroprotection against cerebral ischemia–reperfusion injury, but whether it regulates reactive astrogliosis and glial scar formation is not clear. Methods We exposed cultured astrocytes to oxygen–glucose deprivation/reoxygenation (OGD/R) and used a rat middle cerebral artery occlusion (MCAO)/reperfusion model to investigate the effects of Poly IC. Astrocyte proliferation and proliferation-related molecules were evaluated by immunostaining and Western blotting. Neurological deficit scores, infarct volumes and neuroplasticity were evaluated in rats after transient MCAO. Results In vitro, Poly IC inhibited astrocyte proliferation, upregulated Toll-like receptor 3 (TLR3) expression, upregulated interferon-β, and downregulated interleukin-6 production. These changes were blocked by a neutralizing antibody against TLR3, suggesting that Poly IC function is TLR3-dependent. Moreover, in the MCAO model, Poly IC attenuated reactive astrogliosis, reduced brain infarction volume, and improved neurological function. In addition, Poly IC prevented MCAO-induced reductions in soma size, dendrite length, and number of dendritic bifurcations in cortical neurons of the infarct penumbra. Conclusions By ameliorating astrogliosis-related damage, Poly IC is a potential therapeutic agent for attenuating neuronal damage and promoting recovery after brain ischemia.

The toll-like receptor 3 pathway in homeostasis, responses to injury and wound repair

“…Beneficial effects were also observed in rats, using a similar approach [88]. These data support the potential for TLR3 agonists in brain I/R injury, such as stroke.…”

“…As indicated earlier (see Section 2.3), TLR3 has previously been implicated in mediating loss of BBB integrity and contributing to neuropathology in a mouse model of WNV infection [30]. Nonetheless, recent studies have reported protective effects of poly(IC) treatment in brain I/R injury models [87][88][89]. This was linked to the capacity of TLR3 signalling in human astrocytes to drive expression of anti-inflammatory cytokines, such as Ifn-, which act as neuroprotective factors [87,88].…”

“…Nonetheless, recent studies have reported protective effects of poly(IC) treatment in brain I/R injury models [87][88][89]. This was linked to the capacity of TLR3 signalling in human astrocytes to drive expression of anti-inflammatory cytokines, such as Ifn-, which act as neuroprotective factors [87,88]. More specifically, poly(IC) pre-treatment of mice or primary astrocytes increased cell viability and proliferation, and reduced NF-B activation and inflammatory cytokine production following I/R injury [87,88].…”

“…This was linked to the capacity of TLR3 signalling in human astrocytes to drive expression of anti-inflammatory cytokines, such as Ifn-, which act as neuroprotective factors [87,88]. More specifically, poly(IC) pre-treatment of mice or primary astrocytes increased cell viability and proliferation, and reduced NF-B activation and inflammatory cytokine production following I/R injury [87,88]. This treatment regime also triggered Irf3 phosphorylation and upregulated Ifn-expression, suggesting a role for this signalling arm in injury repair [90].…”

Nucleic acid binding and other biomedical properties of artificial oligolysines

“…29 In addition, poly I:C is a potential therapeutic agent useful for attenuating neuronal damage and promoting recovery after brain ischemia. 30 However, stability issues limit the clinical application of poly rI and poly I:C that undergo facile enzymatic degradation. Hence is the need for technological approaches aimed to improve the delivery and consequent efficacy of these RNAs.…”