Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA.
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA; Department of Pediatrics, Boonshoft School of Medicine, Wright State University, Dayton, Ohio, USA; Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
J Invest Dermatol. 2023 Jul;143(7):1279-1288.e9. doi: 10.1016/j.jid.2022.12.018. Epub 2023 Jan 25.
Although effective in treating actinic damage, topical photodynamic therapy (PDT) has been shown to be immunosuppressive through unknown mechanisms, which could potentially limit its effectiveness. Multiple types of environmental stressors, including PDT, can produce the immunosuppressive lipid mediator platelet-activating factor (PAF). Because PAF can produce subcellular microvesicle particles (MVPs), these studies tested whether PDT can generate PAF and MVP release and whether these are involved in PDT-induced immunosuppression. Previously, topical PDT using blue light and 5-aminolevulinic acid was found to be a potent stimulus for PAF production in mice and human skin explants and human patients, and we show that experimental PDT also generates high levels of MVP. PDT-generated MVPs were independent of the PAF receptor but were dependent on the MVP-generating enzyme acid sphingomyelinase. Patients undergoing topical PDT treatment to at least 10% of body surface area showed local and systemic immunosuppression as measured by inhibition of delayed-type hypersensitivity reactions. Finally, using a murine model of contact hypersensitivity, PDT immunosuppression was blocked by genetic and pharmacologic inhibition of acid sphingomyelinase and genetic inhibition of PAF receptor signaling. These studies describe a mechanism involving MVP through which PDT exerts immunomodulatory effects, providing a potential target to improve its effectiveness.
尽管光动力疗法（PDT）在治疗光化性损伤方面非常有效，但它通过未知机制表现出免疫抑制作用，这可能会限制其疗效。多种类型的环境应激源，包括 PDT，都可以产生具有免疫抑制作用的脂类介质血小板激活因子（PAF）。由于 PAF 可以产生亚细胞微小囊泡颗粒（MVP），因此这些研究测试了 PDT 是否可以产生 PAF 和 MVP 释放，以及这些是否参与 PDT 诱导的免疫抑制。先前的研究发现，使用蓝光和 5-氨基酮戊酸的局部 PDT 是小鼠和人体皮肤外植体以及人体患者 PAF 产生的有效刺激物，并且我们表明实验性 PDT 也会产生高水平的 MVP。由 PDT 产生的 MVP 不依赖于 PAF 受体，但依赖于产生 MVP 的酶酸性鞘磷脂酶。接受局部 PDT 治疗至少 10%体表面积的患者表现出局部和全身免疫抑制，如迟发型超敏反应抑制所测量的。最后，在接触性过敏的小鼠模型中，通过酸性鞘磷脂酶的遗传和药理学抑制以及 PAF 受体信号转导的遗传抑制来阻断 PDT 免疫抑制。这些研究描述了一种涉及 MVP 的机制，通过该机制，PDT 发挥免疫调节作用，为提高其疗效提供了一个潜在的靶点。
