TLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair

Impaired remyelination of demyelinated axons is a major cause of neurological disability. In inflammatory demyelinating disease of the central nervous system (CNS), although remyelination does happen, it is often incomplete, resulting in poor clinical recovery. Poly-IC a known TLR3 agonist and IL-33, a cytokine which is induced by poly-IC are known to influence recovery and promote repair in experimental models of CNS demyelination.

We examined the effect of addition of poly-IC and IL-33 on the differentiation and maturation of oligodendrocyte precursor cells (OPC) cultured in vitro. Both Poly-IC and IL-33 induced transcription of myelin genes and the differentiation of OPC to mature myelin forming cells. Poly-IC induced IL-33 in OPC and addition of IL-33 to in vitro cultures, amplified further, IL-33 expression suggesting an autocrine regulation of IL-33. Poly-IC and IL-33 also induced phosphorylation of p38MAPK, a signaling molecule involved in myelination. Following the induction of gliotoxic injury with lysolecithin to the corpus callosum (CC), treatment of animals with poly-IC resulted in greater recruitment of OPC and increased staining for myelin in areas of demyelination. Also, poly-IC treated animals showed greater expression of IL-33 and higher expression of M2 phenotype macrophages in the CC.

Our studies suggest that poly-IC and IL-33 play a role in myelin repair by enhancing expression of myelin genes and are therefore attractive therapeutic agents for use as remyelinating agents in human demyelinating disease.