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.