Modulation of innate immunity by amyloidogenic peptides: Systematic review of pattern recognition receptors and peptide aggregation state

Abstract

Amyloid formation contributes to the development and progression of multiple aging-associated neurodegenerative disorders. Local amyloidoses are characterized by activation of monocytes and macrophages, phagocytic peptide clearance, and upregulation of pro-inflammatory cytokines. Increasing evidence suggests a role for amyloid-producing gut microbiota – as well as amyloid associated with comorbid type 2 diabetes – in regulation of brain amyloidogenesis. However, it is unclear whether these diverse peptides share common mechanisms of innate immune activation, and which aggregate forms induce a pro-inflammatory response. To evaluate the evidence for specific amyloidogenic peptide species and their associated pattern recognition receptors, we systematically searched Embase, PubMed, and Medline for empiric studies through February 2017. We identified 150 studies of diverse peptides – including amyloid-beta, tau, alpha-synuclein, cellular prion protein, serum amyloid A, islet amyloid polypeptide, and bacterial Curli fibrils – demonstrating scavenger receptor-mediated phagocytosis and templating, Toll-like receptor-mediated inflammasome priming, or inflammasome activation. Activation of TLR2 and NLRP3 was common to most peptides identified. An additional 76 studies implicated soluble species (34%), insoluble fibrils (24%), or both (35%). These reports suggest that both early and late aggregates of diverse amyloid-forming peptides contribute to distinct, evolutionarily conserved pattern recognition events with functional roles in pathogen recognition and antimicrobial defense. Further characterization of the interaction between amyloidogenic peptides and innate immune cells will aid in the development of anti-amyloid and immune-modulating therapies.