Myoloid-Related Protein 8, an Endogenous Ligand of Toll-Like Receptor 4, Is Involved in Epileptogenesis of Mesial Temporal Lobe Epilepsy Via Activation of the Nuclear Factor-κB Pathway in Astrocytes

Na Gan, Lifen Yang, Ahmed Omran, Jing Peng, Liwen Wu, Fang He, Ciliu Zhang, Qiulian Xiang, Huimin Kong, Yupin Ma, Muhammad Usman Ashhab, Xiaolu Deng, Fei Yin

The role of Toll-like receptor 4 (TLR4) in the activation of innate immunity has been extensively studied in the past several years. Here, we are the first to report that myeloid-related protein 8 (MRP8), an endogenous TLR4 ligand, is involved in the epileptogenesis of mesial temporal lobe epilepsy (MTLE). We find that the expression of MRP8, TLR4, and interleukin 1-β (IL-1β) was upregulated in a MTLE model during both acute and chronic disease stages. We next investigated the possible roles played by astrocytes, which have been shown to be the major source of IL-1β during epilepsy. Stimulation via MRP8 led to the induction of IL-1β in astrocytes in vitro, accompanied by the activation of Nuclear Factor-κB, while knockdown of TLR4 or inhibition of NF-κB in astrocytes prevented this IL-1β induction. Thus, MRP8 may potentiate the perpetuation of MTLE by activating the NF-κB pathway in astrocytes, and could be a new target for anticonvulsant therapies.