Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis.

One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis. Hao et al. show that FABP5 expression in keratinocytes promotes psoriasis pathogenesis through enhancing neutrophil infiltration and activation. FABP5 represents a promising therapeutic target for the treatment of psoriasis.

顽固性银屑病的标志之一是皮肤病变中的中性粒细胞浸润。然而，中性粒细胞趋化和激活的详细分子机制仍不清楚。在此，我们证明在人类银屑病和银屑病小鼠模型的皮肤中，表皮脂肪酸结合蛋白（E - FABP，FABP5）显著上调。通过全身性敲除以及角质形成细胞条件性（Krt6a - Cre）敲除小鼠中的FABP5基因，但髓系细胞条件性（LysM - Cre）敲除则不会，可减轻银屑病症状。免疫表型分析表明，FABP5缺乏特异性地减少了Ly6G +中性粒细胞在皮肤中的募集。从机制上讲，活化的角质形成细胞产生趋化因子和细胞因子，以FABP5依赖的方式触发中性粒细胞趋化和激活。蛋白质组学分析进一步确定FABP5与含缬酪肽蛋白（VCP）相互作用，VCP是NF - κB信号激活的关键因子。沉默FABP5、VCP或两者均可抑制NF - κB /中性粒细胞趋化信号。总之，这些数据表明FABP5失调是促进银屑病发病机制中NF - κB信号传导和中性粒细胞浸润的一种分子机制。 郝等人表明，角质形成细胞中FABP5的表达通过增强中性粒细胞浸润和激活来促进银屑病发病。FABP5是治疗银屑病的一个有前景的治疗靶点。