Bilirubin nanomedicine alleviates psoriatic skin inflammation by reducing oxidative stress and suppressing pathogenic signaling
Bilirubin nanomedicine alleviates psoriatic skin inflammation by reducing oxidative stress and suppressing pathogenic signaling
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DOI：
10.1016/j.jconrel.2020.07.015
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发表时间：
2020-09-10
影响因子：
10.8
通讯作者：
Jon, Sangyong
中科院分区：
文献类型：
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作者：
Keum, Hyeongseop;Kim, Tae Woo;Jon, Sangyong
银屑病是一种流行的慢性炎症性皮肤病，其特征在于表皮增厚，伴随着由于角质形成细胞的异常增殖而导致的损伤性红斑、鳞屑和硬结。在银屑病的发展过程中，银屑病病灶内细胞内活性氧（ROS）水平升高，激活促炎信号级联反应。在这里，我们评估了胆红素纳米颗粒（BRNP）的治疗效果和作用方式，基于有效的内源性抗氧化剂胆红素，在临床前银屑病模型。我们发现用BRNP局部治疗银屑病皮损有效地减弱了角质形成细胞内ROS水平的上调，并改善了银屑病的症状。随后的机制研究表明，防止活化的角质形成细胞中的氧化应激抑制了炎症介质的分泌和免疫细胞的募集。随后抗原呈递细胞（APC）成熟标志物、II类主要组织相容性复合物（MHC II类）、分化簇（CD）80和CD 86的表达显著降低，导致幼稚CD 4（+）T细胞分化为产生白细胞介素（IL）-17的T辅助细胞（Th）17细胞的减少。与市售皮质类固醇药物丙酸氯倍他索（CLQ）不同，由内源性抗氧化剂胆红素和批准的聚合物聚乙二醇（PEG）组成的BRNP不会产生全身细胞毒性。总的来说，这些发现突出了BRNP作为一种新型纳米药物通过局部治疗改善银屑病样皮肤炎症的潜力，并表明它们的用途可以进一步扩展到治疗其他慢性皮肤炎症疾病，包括特应性皮炎。
Psoriasis is a prevalent chronic inflammatory skin disease characterized by thickening of the epidermis accompanied by lesional erythema, scaling, and induration as a result of abnormal proliferation of keratinocytes. During the development of psoriasis, levels of intracellular reactive oxygen species (ROS) within psoriatic lesions are elevated, activating a pro-inflammatory signaling cascade. Here, we evaluated the therapeutic efficacy and mode of action of bilirubin nanoparticles (BRNPs), based on the potent, endogenous antioxidant bilirubin, in a preclinical psoriasis model. We found that topical treatment of psoriatic lesions with BRNPs effectively attenuated upregulation of intracellular ROS levels within keratinocytes and ameliorated the symptoms of psoriasis. A subsequent mechanistic study showed that preventing oxidative stress in activated keratinocytes suppressed the secretion of inflammatory mediators and recruitment of immune cells. Subsequent expression of the antigen-presenting cell (APC) maturation markers, class II major histocompatibility complex (MHC class II), cluster of differentiation (CD) 80 and CD86, was significantly decreased, resulting in a reduction in the differentiation of naive CD4(+) T cells into interleukin (IL)-17-producing T-helper (Th) 17 cells. Unlike the commercial corticosteroid drug, clobetasol propionate (CLQ), BRNPs, composed of the endogenous antioxidant bilirubin and the approved polymer polyethylene glycol (PEG), did not exert systemic cytotoxicity. Collectively, these findings highlight the potential of BRNPs as a novel nanomedicine for ameliorating psoriasis-like skin inflammation through topical treatment and suggest that their use could be further expanded to treat other chronic skin inflammation diseases, including atopic dermatitis.