Abstract：
Psoriasis is an incurable autoimmune disease that affects 2-3% of the world\'s population. Limited understanding of its pathogenesis hinders the development of therapies for the disease. Herein, we reported that N-acylethanolamine acid amidase (NAAA), a cysteine enzyme that catalyzes the hydrolysis of fatty acid ethanolamides (FAEs), was upregulated in psoriasis patients and imiquimod (IMQ)-induced mouse model of psoriasis. The upregulated NAAA contributes to the progression of psoriasis via enhancing dendritic cell (DCs) maturation. Transgenic expression of NAAA in mice accelerated the development of psoriasis, whereas genetic ablation of NAAA or local administration of NAAA inhibitor F96 ameliorated psoriasis. NAAA expressed in dendritic cells (DCs), but not in macrophages, T cells, or keratinocytes plays a critical role in psoriasis development. In addition, the results showed that NAAA degrades palmitoylethanolamide (PEA) and reduces PEA-PPARα-mediated dissociation of NF-κB p65 from Sirtuin 1 (SIRT1), subsequently, repressing the acetylation of p65 and down-regulating IL10 production. The decreased IL10 then leads to the maturation of DCs, thus promoting the development of psoriasis. These results provide new insights into the pathophysiological mechanism of psoriasis and identify NAAA as a novel target for the treatment of psoriasis.
摘要：
牛皮癣是一种无法治愈的自身免疫性疾病，影响全球2-3%的人口。对其发病机理的有限理解阻碍了该疾病疗法的发展。在这里，我们报道了N-酰基乙醇胺酸酰胺酶（NAAA），一种催化脂肪酸乙醇酰胺（FAEs）水解的半胱氨酸酶，在银屑病患者和咪喹莫特（IMQ）诱导的银屑病小鼠模型中上调。上调的NAAA通过增强树突状细胞(DC)成熟促进银屑病的进展。NAAA在小鼠体内的转基因表达加速了银屑病的发展,而NAAA的遗传消融或NAAA抑制剂F96的局部给药可改善银屑病。NAAA在树突状细胞（DC）中表达，但不是在巨噬细胞中，T细胞,或角质形成细胞在牛皮癣的发展中起关键作用。此外,结果表明，NAAA降解棕榈酰乙醇胺（PEA）并减少PEA-PPARα介导的NF-κBp65从Sirtuin1（SIRT1）的解离，随后,抑制p65的乙酰化并下调IL10的产生。减少的IL10然后导致DCs的成熟，从而促进银屑病的发展。这些结果为银屑病的病理生理机制提供了新的见解，并将NAAA确定为治疗银屑病的新靶点。
