Rodent and cell culture studies suggest that HMGB1 (which activates TLR4, RAGE, and Mac1), S100B (primarily of astrocyte origin, also a RAGE ligand), and oligomeric ASYN (a ligand for TLR2 released by dying neurons) contribute to chronic microglial activation in PD [49,52,53,54,55,56,57,58,59,60]. This evidence concerns the gene ITGAM and Parkinson disease.