Selective inhibition of NLRP3 inflammasome by designed peptide originating from ASC

Abstract NACHT, LRR, and PYD domains‐containing protein 3 (NLRP3) inflammasome is a multiprotein complex which forms within cells in response to various microbial and self‐derived triggers. Mutations in the gene encoding NLRP3 cause rare cryopyrin‐associated periodic syndromes (CAPS) and growing evidence links NLRP3 inflammasome to common diseases such as Alzheimer´s disease. In order to modulate different stages of NLRP3 inflammasome assembly nine peptides whose sequences correspond to segments of inflammasome components NLRP3 and apoptosis‐associated speck‐like protein containing a CARD (ASC) were selected. Five peptides inhibited IL‐1β release, caspase‐1 activation and ASC oligomerization in response to soluble and particulate NLRP3 triggers. Modulatory peptides also attenuated IL‐1β maturation induced by constitutive CAPS‐associated NLRP3 mutants. Peptide corresponding to H2‐H3 segment of ASC pyrin domain selectively inhibited NLRP3 inflammasome by binding to NLRP3 pyrin domain in the micromolar range. The peptide had no effect on AIM2 and NLRC4 inflammasomes as well as NF‐κB pathway. The peptide effectively dampened neutrophil infiltration in the silica‐induced peritonitis and when equipped with Antennapedia or Angiopep‐2 motifs crossed the blood‐brain barrier in a mouse model. Our study demonstrates that peptides represent an important tool for targeting multiprotein inflammatory complexes and can serve as the basis for the development of novel anti‐inflammatory strategies for neurodegeneration.