Alpha-synuclein (αS) functions as an alarmin to promote inflammatory and immune responses by activating dendritic cells and macrophages

Abstract Alpha-synuclein (αS) is causally involved in the development of neurodegenerative disorders including Parkinson’s disease (PD). Recently, αS has been shown to be a chemotactic activator of phagocytes. Here, we report that αS is a critical mediator of inflammatory and immune responses. Treatment with αS activated human and mouse dendritic cells (DCs) and macrophages at both phenotypic and functional levels. αS treatment of DCs triggered the NF-κB signaling pathway and predominantly enhanced their Th1-polarizing capacity. αS also polarized mouse macrophages in an M1 direction. Activation of APCs by αS was mediated by TLR4. Intraperitoneal administration of αS recruited DCs and macrophages into the peritoneal cavity, while inflammatory reactions in the peritoneal cavity and colons induced αS expression and production. Importantly, immunization with ovalbumin (OVA) in the presence of αS promoted OVA-specific antibody and T cell responses, whereas the induction of inflammatory and OVA-specific immune responses was markedly reduced in αS−/− mice. Thus, αS can be considered an alarmin that functions as a mediator of inflammatory and immune responses. The potent proinflammatory and immunostimulating effects of αS in the periphery may cause the accumulation of αS and inflammatory damage in the central nervous system, culminating in Parkinson disease (PD).