Modulation of Innate Immunity by Amyloidogenic Peptides.

Amyloid formation contributes to the development of progressive metabolic and neurodegenerative diseases, while also serving functional roles in host defense. Emerging evidence suggests that as amyloidogenic peptides populate distinct aggregation states, they interact with different combinations of pattern recognition receptors (PRRs) to direct the phenotype and function of tissue-resident and infiltrating innate immune cells. We review recent evidence of innate immunomodulation by distinct forms of amyloidogenic peptides produced by mammals (humans, non-human primates), bacteria, and fungi, as well as the corresponding cell-surface and intracellular PRRs in these interactions, in human and mouse models. Our emerging understanding of peptide aggregate-innate immune cell interactions, and the factors regulating the balance between amyloid function and pathogenicity, might aid the development of anti-amyloid and immunomodulating therapies. Amyloidogenic peptides of both bacterial and mammalian origin transition through multiple aggregation states with distinct effects on mononuclear phagocyte function, commonly mediated by TLR2 and NLRP3. Promising therapeutic agents target such macrophage/peptide interactions. Disease-associated amyloidogenic peptides may act as antimicrobial peptides. Soluble oligomers bind microbial cell walls, protofibrils limit adhesion to host cells, and fibrils wall off invading pathogens. Infectious or sterile inflammatory stimuli may partially drive amyloidosis, a hypothesis supported by cross-seeding of endogenous amyloid formation by products of innate immune cell activation: apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) specks and neutrophil extracellular traps (NETs). Cross-seeding can also occur between amyloids in different tissues, such as the gut and brain, and across species. Manipulation of microbial amyloids might be a potential therapeutic approach to treat amyloid and inflammatory diseases. [ABSTRACT FROM AUTHOR]