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As with corneal infections, severe or prolonged inflammation jeopardizes corneal transparency, leading to devastating vision loss. We hypothesized that keratin 6a\u2013derived 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\u2013 and 18\u2013amino acid sequences suppressed lipoteichoic acid (LTA)\u2013 and lipopolysaccharide (LPS)\u2013induced NF\u03baB 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.<\/jats:p>","DOI":"10.1126\/scitranslmed.ade2909","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T13:58:08Z","timestamp":1678283888000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":37,"title":["Simultaneous control of infection and inflammation with keratin-derived antibacterial peptides targeting TLRs and co-receptors"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3423-094X","authenticated-orcid":true,"given":"Yan","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Ophthalmic Research, Cole Eye Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, 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