The use and the timing of initiation of steroids for controlling unwanted infectious inflammation are major clinical dilemmas due to their possible adverse effects including delayed microbial clearance and wound healing. Compounding this difficulty is the continued emergence of drug-resistant bacteria; yet anti-infective strategies aiming at augmenting inflammatory responses to facilitate bacterial killing cannot be used to treat infections involving vulnerable tissues. As is the case with bacterial keratitis, excessive inflammation jeopardizes corneal transparency leading to devastating vision loss. Hence, a two-pronged remedy possessing both anti-infective and anti-inflammatory properties would be helpful for tackling antibiotic resistance and enabling prompt inflammation control at once. Using murine primary neutrophils, macrophages and sterile corneal inflammation models, we found that non-toxic and pro-healing human keratin 6a-derived antimicrobial peptides (KAMPs) with a native 10- or 18-amino-acid sequence suppress LTA- and LPS-induced NF-κB and IRF3 activation, proinflammatory cytokine production, as well as phagocyte recruitment, independently of their bactericidal function. Mechanistically, direct binding of KAMPs to cell surface TLR2 and TLR co-receptors CD14 and MD-2 not only blocks their bacterial ligand docking sites, but also reduces cell surface availability of TLR2 and TLR4 through promotion of receptor endocytosis. Benefitting from the dual functions of topical KAMPs, experimental bacterial keratitis caused was effectively prevented or controlled, as evidenced by significant reductions of corneal opacification and inflammatory cell infiltration in addition to enhanced bacterial clearance. These findings reveal multiple TLR-targeting activities of KAMPs and demonstrate their therapeutic potential as a multifunctional drug for managing sterile and infectious inflammatory diseases.

中文翻译：

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通过角质蛋白衍生的抗菌肽（KAMPs）靶向TLR和共受体同时控制感染和炎症

用于控制有害的感染性炎症的类固醇的使用及其时机是主要的临床难题，因为它们可能产生不利影响，包括延迟的微生物清除和伤口愈合。使这种困难更加复杂的是耐药菌的不断出现。然而，旨在增强炎症反应以促进细菌杀灭的抗感染策略不能用于治疗涉及脆弱组织的感染。与细菌性角膜炎一样，过度的炎症会损害角膜透明性，导致毁灭性的视力丧失。因此，同时具有抗感染和抗炎特性的两管齐下的药物将有助于解决抗生素耐药性，并能迅速控制炎症。使用鼠类中性粒细胞 巨噬细胞和无菌角膜炎症模型，我们发现具有天然10或18个氨基酸序列的无毒且可治愈人角蛋白6a的抗菌肽（KAMPs）抑制LTA和LPS诱导的NF-κB和IRF3激活，促炎细胞因子的产生以及吞噬细胞募集，与它们的杀菌功能无关。从机制上讲，KAMP与细胞表面TLR2和TLR共受体CD14和MD-2的直接结合不仅阻断了它们的细菌配体对接位点，而且通过促进受体内吞作用降低了TLR2和TLR4的细胞表面利用率。得益于局部KAMP的双重功能，可以有效地预防或控制实验性细菌性角膜炎，除增加细菌清除率外，还明显减少了角膜混浊和炎性细胞浸润。这些发现揭示了KAMP的多种TLR靶向活性，并证明了它们作为用于治疗无菌和传染性炎症疾病的多功能药物的治疗潜力。