Pentraxins interact with misfolded proteins and inhibit aberrant innate immune activation (INC1P.361)

Abstract

Abstract Amyloid deposition is linked to different diseases, including Alzheimer’s disease and systemic amyloidosis. How misfolded proteins, including amyloid and its in-process products, are controlled by the host remains obscure. Pentraxins are multimeric pattern recognition proteins that bind to diverse ligands and promote the clearance of microbes. Serum amyloid P-component (SAP), a short chain pentraxin, associates with amyloid deposits in patients. We hypothesize that pentraxins may interact with different forms of misfolded proteins and modulate their biological impact. We found that human SAP readily bound to all types of amyloids, including protein-only, DNA-containing or heparin-containing fibrils. This interaction depended on the presence of calcium. Interestingly, both SAP and C-reactive protein (CRP), another pentraxin, bound to soluble amyloid precursor (AP) protein in the absence of divalent cations. Furthermore, SAP decamer recognized AP whereas aggregated SAP preferentially associated with amyloid. The misfolded structure in AP was necessary for binding to SAP and CRP. DNA-containing amyloid (A-DNA) triggers type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) and promotes lupus-like disease. Binding of SAP to A-DNA inhibited the production of IFN-I by human pDCs. Altogether, our data suggest that pentraxins differentially interact with various forms of misfolded proteins and modulate their ability to stimulate aberrant innate immune activation.