LAUSR

Controlling infection-driven inflammation is a major clinical dilemma because of limited therapeutic options and possible adverse effects on microbial clearance. Compounding this difficulty is the continued emergence of drug-resistant bacteria, where experimental strategies aiming to augment inflammatory responses for enhanced microbial killing are not applicable treatment options for infections of vulnerable organs. As with corneal infections, severe or prolonged inflammation jeopardizes corneal transparency, leading to devastating vision loss. We hypothesized that keratin 6a–derived antimicrobial peptides (KAMPs) may be a two-pronged remedy capable of tackling bacterial infection and inflammation at once. We used murine peritoneal neutrophils and macrophages, together with an in vivo model of sterile corneal inflammation, to find that nontoxic and prohealing KAMPs with natural 10– and 18–amino acid sequences suppressed lipoteichoic acid (LTA)– and lipopolysaccharide (LPS)–induced NFκB and IRF3 activation, proinflammatory cytokine production, and phagocyte recruitment independently of their bactericidal function. Mechanistically, KAMPs not only competed with bacterial ligands for cell surface Toll-like receptor (TLR) and co-receptors (MD2, CD14, and TLR2) but also reduced cell surface availability of TLR2 and TLR4 through promotion of receptor endocytosis. Topical KAMP treatment effectively alleviated experimental bacterial keratitis, as evidenced by substantial reductions of corneal opacification, inflammatory cell infiltration, and bacterial burden. These findings reveal the TLR-targeting activities of KAMPs and demonstrate their therapeutic potential as a multifunctional drug for managing infectious inflammatory disease. Description Bifunctional keratin peptides deliver a one-two punch to alleviate inflammation and infection and avoid functional damage in corneal tissue. Combating corneal infections Infection-driven corneal inflammation can result in scarring that leads to impaired vision, making effective treatment a top priority in the face of growing antibiotic resistance. Sun et al. show that antimicrobial peptides derived from the human protein keratin 6a reduce inflammatory cell infiltration while still lowering infection burden in corneal tissues. Therapeutic administration of the anti-inflammatory, antimicrobial peptides in eyedrops improved bacterial clearance and cornea transparency in bacterial keratitis mouse models established with either Pseudomonas aeruginosa or Staphylococcus aureus, suggesting potential for clinical translation. —CAC