The Effect of Retinoic Acid on Neutrophil Innate Immune Interactions With Cutaneous Bacterial Pathogens.

IF 2 Q3 INFECTIOUS DISEASES Infectious microbes & diseases Pub Date : 2024-06-01 Epub Date: 2024-04-29 DOI:10.1097/im9.0000000000000145
Alexandra Stream, Ross Corriden, Simon Döhrmann, Richard L Gallo, Victor Nizet, Ericka L Anderson
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Abstract

Vitamin A and its biologically active derivative, retinoic acid (RA), are important for many immune processes. RA, in particular, is essential for the development of immune cells, including neutrophils, which serve as a front-line defense against infection. While vitamin A deficiency has been linked to higher susceptibility to infections, the precise role of vitamin A/RA in host-pathogen interactions remains poorly understood. Here, we provided evidence that RA boosts neutrophil killing of methicillin-resistant Staphylococcus aureus (MRSA). RA treatment stimulated primary human neutrophils to produce reactive oxygen species, neutrophil extracellular traps, and the antimicrobial peptide cathelicidin (LL-37). Because RA treatment was insufficient to reduce MRSA burden in an in vivo murine model of skin infection, we expanded our analysis to other infectious agents. RA did not affect the growth of a number of common bacterial pathogens, including MRSA, Escherichia coli K1 and Pseudomonas aeruginosa; however, RA directly inhibited the growth of group A Streptococcus (GAS). This antimicrobial effect, likely in combination with RA-mediated neutrophil boosting, resulted in substantial GAS killing in neutrophil killing assays conducted in the presence of RA. Furthermore, in a murine model of GAS skin infection, topical RA treatment showed therapeutic potential by reducing both skin lesion size and bacterial burden. These findings suggest that RA may hold promise as a therapeutic agent against GAS and perhaps other clinically significant human pathogens.

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维甲酸对中性粒细胞与皮肤细菌病原体的先天性免疫相互作用的影响
维生素 A 及其生物活性衍生物视黄酸(RA)对许多免疫过程都很重要。尤其是视黄酸,它对包括中性粒细胞在内的免疫细胞的发育至关重要,而中性粒细胞是抵御感染的第一道防线。虽然维生素 A 缺乏与感染易感性增高有关,但人们对维生素 A/RA 在宿主与病原体相互作用中的确切作用仍然知之甚少。在这里,我们提供的证据表明,RA 能增强中性粒细胞对耐甲氧西林金黄色葡萄球菌(MRSA)的杀伤力。RA治疗刺激原代人中性粒细胞产生活性氧、中性粒细胞胞外捕获物和抗菌肽cathelicidin(LL-37)。由于在体内小鼠皮肤感染模型中,RA 治疗不足以减轻 MRSA 的负担,因此我们将分析范围扩大到了其他感染病原体。RA 不影响一些常见细菌病原体的生长,包括 MRSA、大肠杆菌 K1 和铜绿假单胞菌;但 RA 能直接抑制 A 组链球菌(GAS)的生长。这种抗菌作用可能与 RA 介导的中性粒细胞增殖相结合,在有 RA 存在的情况下进行的中性粒细胞杀伤试验中,GAS 被大量杀死。此外,在小鼠皮肤感染 GAS 的模型中,局部 RA 治疗通过减少皮损面积和细菌负担而显示出治疗潜力。这些研究结果表明,RA 有可能成为一种治疗 GAS 的药物,或许还能治疗其他临床上常见的人类病原体。
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