Simultaneous control of infection and inflammation with keratin-derived antibacterial peptides targeting TLRs and...

Area of Science:

• Immunology
• Microbiology
• Ophthalmology

Background:

• Controlling infection-driven inflammation presents a clinical challenge due to limited therapies and potential adverse effects on microbial clearance.
• Emerging drug-resistant bacteria further complicate treatment, especially for vulnerable organs like the cornea, where inflammation can cause vision loss.

Purpose of the Study:

• To investigate keratin 6a-derived antimicrobial peptides (KAMPs) as a potential dual-action therapy for bacterial infections and inflammation.
• To explore the anti-inflammatory and therapeutic mechanisms of KAMPs in corneal infections.

Main Methods:

• Utilized murine peritoneal neutrophils and macrophages, and an in vivo model of sterile corneal inflammation.
• Assessed KAMPs' effects on lipoteichoic acid (LTA) and lipopolysaccharide (LPS)-induced inflammatory pathways (NFκB, IRF3) and cytokine production.
• Investigated KAMPs' interaction with Toll-like receptors (TLRs) and their impact on receptor availability and endocytosis.
• Evaluated topical KAMP treatment in a bacterial keratitis model.

Main Results:

• Nontoxic KAMPs suppressed LTA- and LPS-induced NFκB and IRF3 activation, proinflammatory cytokine production, and phagocyte recruitment, independent of bactericidal activity.
• KAMPs competed with bacterial ligands for TLRs and co-receptors (MD2, CD14, TLR2) and reduced cell surface TLR2 and TLR4 via endocytosis promotion.
• Topical KAMP treatment significantly reduced corneal opacification, inflammatory cell infiltration, and bacterial burden in experimental bacterial keratitis.

Conclusions:

• KAMPs exhibit potent anti-inflammatory effects by targeting TLR signaling pathways.
• KAMPs demonstrate therapeutic potential as multifunctional agents for managing infectious inflammatory diseases, particularly bacterial keratitis.