Alpha-synuclein (αS) acts as an alarmin to promote dendritic cell activation and proinflammatory immune response

Abstract

Abstract Alpha-synuclein (αS) protein is involved in the development of neurodegenerative disorders including Parkinson’s disease. Recently, it has been shown that αS expression by enteric neurites in the inflamed tissues of the gut correlates with the degree of inflammation and αS is chemotactic for phagocytes. However, it is not clear whether αS plays any roles in immune responses. Here, we report that αS has potent immunopromoting activity. Treatment of human monocyte derived dendritic cells (Mo-DCs) by αS resulted in upregulation of costimulatory (CD80, CD83, & CD86) and MHC (HLA-ABC & HLA-DR) molecules and production of proinflammatory cytokines such as IL-12 and TNFα. αS activated NF-κB signaling pathways in DCs and conditioned DCs to potentiate Th1 and Th17 polarization of CD4+ T cells in an allogeneic MLR. αS also induced mouse bone marrow derived (BM)-DCs and macrophages in a Th1-polarizing and M1 direction, respectively. αS activation of APCs is mediated by the TLR4-MYD88 signaling pathways. In an in vivo setting, administration of αS induced the recruitment of APCs at the site of injection. Furthermore, αS enhanced the induction of OVA-specific antibody and T cell responses when mice were immunized with a mixture of OVA and αS. Based on the ability of αS to recruit APCs to the site of administration and to promote antigen-specific immune responses, αS can be considered an alarmin capable of promoting the development of innate and adaptive immune responses. Thus, αS, in addition to acting as an inducer of neurodegenerative diseases, exerts a potent previously unappreciated proinflammatory and immunostimulating effect.