Arginine-Rich Peptides Regulate the Pathogenic Galectin-10 Crystallization and Mitigate Crystallopathy-Associated Inflammation.

Protein self-assembly into a crystal in vivo triggers acute or chronic organ injury that can lead to intractable diseases lacking specific treatment options. In this study, we report the discovery of ionic arginine-rich peptides to disrupt the pathogenic galectin-10 (gal-10) crystallization, where the aberrant deposition of gal-10 crystals in airways causes the activation of IL-1β-dependent inflammation and the stimulation of epithelial cells to produce TNF-α. Gal-10 crystals show susceptibility to pH changes and charged residue substitutions at the protein packing interfaces, manifesting the role of charge-charge attractions across protein-protein interaction interfaces in governing gal-10 crystallization. To dissolve the gal-10 crystal, the ionic peptides R9 and R12Y8 were identified to eliminate the interprotein charge-charge interactions. The efficacy of R12Y8 in mitigating the gal-10 crystallopathy in vivo was assessed in a crystal-induced lung inflammation mice model. The mice intratracheally administrated by R12Y8 exhibited a downregulated release of proinflammatory cytokines and reduced infiltration of inflammatory cells in the lungs. Our study demonstrates that the pathogenic gal-10 crystallization is readily eliminated by R-rich peptides, which may display translational potentials for the treatment of gal-10 crystallopathy.