Schematic of the viscous cycle between inflammation and Lewy pathology. Schematic illustration demonstrating how a variety of factors including the implantation of foreign tissue could cause microglia to become activated and initiate a vicious cycle in which toxic cytokines cause native α-synuclein to misfold, and the uptake of misfolded α-synuclein causes microglia to become activated. In this scenario, microglia become activated and release toxic cytokines, which can metabolize and cleave native α-synuclein causing it to misfold, aggregate, and form pathological inclusions (Lewy pathology). Misfolded α-synuclein can be released from cells and taken up by microglia causing them to become activated with the release of toxic cytokines, thereby perpetuating the vicious cycle. The release of different toxic cytokines from microglia may cause α-synuclein to form and fold differently to cause the known diversity of pathological species of α-synuclein. In addition, cytokine release might affect α-synuclein in nearby cells in a similar manner, thus facilitating the selective spread and propagation of α-synuclein pathology in vulnerable cell populations. This vicious cycle could explain why α-synuclein pathology developed in implanted dopamine neurons in Parkinson’s disease patients, how templating occurs in Parkinson’s disease, and how toxic cytokines may be involved in the spread of α-synuclein pathology.