Abstract：
Amino acid (aa) metabolism is closely correlated with the pathogenesis of psoriasis; however, details on aa transportation during this process are barely known. Here, we find that SLC38A5, a sodium-dependent neutral aa transporter that counter-transports protons, is markedly upregulated in the psoriatic skin of both human patients and mouse models. SLC38A5 deficiency significantly ameliorates the pathogenesis of psoriasis, indicating a pathogenic role of SLC38A5. Surprisingly, SLC38A5 is almost exclusively expressed in dendritic cells (DCs) when analyzing the psoriatic lesion and mainly locates on the lysosome. Mechanistically, SLC38A5 potentiates lysosomal acidification, which dictates the cleavage and activation of TLR7 with ensuing production of pro-inflammatory cytokines such as interleukin-23 (IL-23) and IL-1β from DCs and eventually aggravates psoriatic inflammation. In summary, this work uncovers an auxiliary mechanism in driving lysosomal acidification, provides inspiring insights for DC biology and psoriasis etiology, and reveals SLC38A5 as a promising therapeutic target for treating psoriasis.
摘要：
氨基酸(aa)代谢与银屑病的发病机制密切相关;在这个过程中，关于aa运输的细节鲜为人知。这里,我们发现SLC38A5是一种依赖钠的中性aa转运蛋白，可以反向运输质子，在人类患者和小鼠模型的牛皮癣皮肤中明显上调。SLC38A5缺乏显着改善银屑病的发病机制，表明SLC38A5的致病作用。令人惊讶的是,在分析银屑病病变时,SLC38A5几乎仅在树突状细胞(DC)中表达,并且主要位于溶酶体上。机械上,SLC38A5增强溶酶体酸化，这决定了TLR7的裂解和活化，随后从DC中产生促炎细胞因子，如白介素-23（IL-23）和IL-1β，并最终加重银屑病炎症。总之,这项工作揭示了驱动溶酶体酸化的辅助机制，为DC生物学和牛皮癣病因学提供了鼓舞人心的见解，并揭示了SLC38A5作为治疗银屑病的一个有希望的治疗靶点。
