Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis.
Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis.
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DOI：
10.1371/journal.ppat.1000826
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发表时间：
2010-03-26
期刊：
影响因子：
6.7
通讯作者：
Pier GB
中科院分区：
文献类型：
--
作者：
Gadjeva M;Nagashima J;Zaidi T;Mitchell RA;Pier GB
铜绿假单胞菌引起严重的威胁视力的角膜感染，对病原体的炎症反应是导致角膜损伤的主要因素，导致视力丧失。我们发现，缺乏巨噬细胞移动抑制因子（MIF）（炎症的关键调节因子）的小鼠，急性铜绿假单胞菌角膜炎的后果显着减少。当将铜绿假单胞菌感染的MIF敲除（KO）小鼠与感染的野生型小鼠进行比较时，结果的这种改善表现为细菌清除的改善、中性粒细胞浸润的减少和炎症反应的减少。应用于感染角膜的重组MIF恢复了MIF缺陷小鼠对铜绿假单胞菌诱导的疾病的易感性，表明MIF是必要的，足以在该免疫豁免部位引起显著的病理学。在铜绿假单胞菌诱导的感染期间给予MIF抑制剂改善了疾病相关的病理学。MIF通过增强响应铜绿假单胞菌感染的促炎介质的合成以及通过促进角膜上皮细胞的细菌侵袭（角膜炎模型中的毒力相关物）来调节上皮细胞对感染的响应。我们的研究结果揭示了一种宿主因子，它可以增强炎症并传播细菌细胞入侵，并进一步表明在感染期间抑制MIF可能具有有益的治疗效果。 铜绿假单胞菌可引起导致视觉功能迅速丧失的感染。目前的治疗包括抗生素治疗，减少细菌负荷;然而，由于不受控制的炎症，组织损伤发生。因此，需要将联合收割机抗微生物治疗与抗炎治疗相结合的新的治疗方法。我们的实验发现，巨噬细胞移动抑制因子（MIF）缺陷的小鼠从急性细菌感染中恢复的效率高于野生型对照小鼠。这种改善表现为与铜绿假单胞菌感染的野生型对照小鼠相比，MIF敲除小鼠的细菌清除率提高，炎症反应降低。我们发现，治疗感染的小鼠与MIF活性的小分子抑制剂感染后，促进疾病的恢复。这种方法将有助于产生新的治疗策略的细菌性角膜炎。
Pseudomonas aeruginosa causes severe sight-threatening corneal infections, with the inflammatory response to the pathogen being the major factor resulting in damage to the cornea that leads to loss of visual acuity. We found that mice deficient for macrophage migration inhibitory factor (MIF), a key regulator of inflammation, had significantly reduced consequences from acute P. aeruginosa keratitis. This improvement in the outcome was manifested as improved bacterial clearance, decreased neutrophil infiltration, and decreased inflammatory responses when P. aeruginosa-infected MIF knock out (KO) mice were compared to infected wild-type mice. Recombinant MIF applied to infected corneas restored the susceptibility of MIF deficient mice to P. aeruginosa-induced disease, demonstrating that MIF is necessary and sufficient to cause significant pathology at this immune privileged site. A MIF inhibitor administered during P. aeruginosa-induced infection ameliorated the disease-associated pathology. MIF regulated epithelial cell responses to infection by enhancing synthesis of proinflammatory mediators in response to P. aeruginosa infection and by promoting bacterial invasion of corneal epithelial cells, a correlate of virulence in the keratitis model. Our results uncover a host factor that elevates inflammation and propagates bacterial cellular invasion, and further suggest that inhibition of MIF during infection may have a beneficial therapeutic effect. Pseudomonas aeruginosa can induce infections that lead to a rapid loss of visual function. The current therapy includes antibiotic treatment which reduces the bacterial burden; nevertheless, tissue damage occurs as a result of an uncontrolled inflammation. Therefore, new therapeutic approaches are needed that will combine antimicrobial treatment with anti-inflammatory treatment. Our experiments have uncovered that mice deficient for macrophage migration inhibitory factor (MIF) recovered from acute bacterial infection more efficiently than wild-type control mice. This improvement was manifested as improved bacterial clearance, and decreased inflammatory responses in the MIF knockouts when compared to P. aeruginosa-infected wild-type control mice. We find that treatment of the infected mice with small molecule inhibitor of MIF activity after the onset of the infection promoted recovery from disease. This approach will facilitate generation of novel treatment strategies for bacterial keratitis.
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