Toll-Like Receptor-3 Activation Increases the Vulnerability of the Neonatal Brain to Hypoxia-Ischemia

Abstract

Susceptibility and progression of brain injury in the newborn is closely associated with an exacerbated innate immune response, but the underlying mechanisms are often unclear. Toll-like receptors (TLRs) are important innate immune sensors that may influence the vulnerability of the developing brain. In the current study, we provide novel data to show that activation of the viral innate immune receptor TLR-3 sensitizes the neonatal brain to subsequent hypoxic-ischemic (HI) damage. Poly inosinic:poly cytidylic acid (Poly I:C), a synthetic ligand for TLR-3, was administered to neonatal mice 14 h before cerebral HI. Activation of TLR-3 before HI increased infarct volume from 3.0 Ϯ 0.5 to 15.4 Ϯ 2.1 mm 3 and augmented loss of myelin basic protein from 13.4 Ϯ 6.0 to 70.6 Ϯ 5.3%. The sensitizing effect of Poly I:C was specific for the TLR-3 pathway because mice deficient in the TLR-3 adaptor protein Toll/IL-1R domain-containing adaptor molecule-1 (TRIF) did not develop larger brain damage. The increased vulnerability was associated with a TRIF-dependent heightened inflammatory response, including proinflammatory cytokines, chemokines, and the apoptosis-associated mediator Fas, whereas there was a decrease in reparative M2-like CD11b ϩ microglia and phosphorylation of Akt. Because TLR-3 is activated via double-stranded RNA during most viral infections, the present study provides evidence that viral infections during pregnancy or in the neonate could have great impact on subsequent HI brain injury.

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

“…It has been reported that poly(I:C) preconditioning could reduce I/R injury (17,18), and our results demonstrated that poly(I:C) treatment 3 h after ischemia had therapeutic effects on cerebral I/R injury. However, a recent study has reported that TRL3 activation increased the susceptibility of neonatal brain to hypoxia and ischemia (36). The precise reasons of the observed differences of these results were not completely clear, which may be related to different animals, models, and dose of poly(I:C).…”

Inflammation‐induced sensitization of the brain in term infants

“…59 More recently, other innate immunity receptors have also been implicated, including TLR3 and the downstream adaptor molecule TRIF. 58 Systemic administration of IL-9 in neonates has also been shown to induce sensitization to excitotoxic brain damage. 61 IL-9 is a Th2 cytokine and was found to be elevated in the plasma of a subset of neonates who later developed CP and did not have elevated levels of pro-inflammatory cytokines.…”

“…56,57 In the hypoxic-ischaemic model, systemic injection of low and non-injurious doses of a toll-like receptor (TLR) 4 or TLR3 agonist (Escherichia coli-derived lipopolysaccharide [LPS] or polyinosinic:polycytidylic acid, respectively), 4 hours before a typically non-injurious hypoxic-ischaemic insult (lasting 20min), induced massive hemispheric brain damage. 21,58 Administering an agent with anti-inflammatory properties, or disabling the TLR inflammatory pathway, reduced the severity of the LPS sensitization. 59,60 These studies demonstrate that exposure to inflammation prior to a moderate hypoxic-ischaemic insult is sufficient, through a sensitization process, to make the newborn brain extremely susceptible to damage.…”

A Critical Review of Models of Perinatal Infection

“…to P3-P11 mice also resulted in a transient decrease in volumes of the gray and white matter in the forebrain and of the molecular layer in the cerebellum; these changes were normalized by P53 [96]. In addition to a direct neurotoxic effect of infection/inflammation, several studies have demonstrated that LPS or poly(I:C) can sensitize the brain to subsequent injury following hypoxia-ischemia [65,97]. This increased vulnerability of the neonatal brain to LPS has been attributed to IL-1β [98].…”