Figure 4.

Mechanisms of TLR4 and TLR3 sensitization. TLR4 increases vulnerability of the immature CNS through activation of the MyD88-dependent pathway, leading to NF-κB-dependent production of IL-1β and TNF and activation of JNK. Endosomal TLR3 induces sensitization through TRIF-dependent activation of NF-κB, IRF and apoptosis, and inhibition of potentially cytoprotective CD206⁺ cells.²⁷ LPS and hypoxia–ischaemia induce proteolytic activity of tPA, but this can be blocked by CPAI, which reduces NF-κB signalling, microglial activation, and production of proinflammatory cytokines in the brain.¹²⁶ JNK inhibition also significantly reduces neuroinflammation, blood–brain barrier leakage and oligodendrocyte progenitor apoptosis¹²⁷ after LPS sensitization. Abbreviations: CPAI, plasminogen activator protein-1; IRF, interferon regulatory factor; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; Myd88, myeloid differentiation factor 88; NF-κB, nuclear factor-κB; TLR, Toll-like receptor; TNF, tumour necrosis factor; tPA, tissue plasminogen activator; TRIF, TIR-domain-containing adapter-inducing IFN-β.