临床研究表明，非酒精性脂肪性肝炎（NASH）与银屑病存在双向关联，相互影响其发展和严重程度。在此，我们使用小鼠模型探索了NASH与银屑病之间的双向因果关系。通过在出生后2天注射链脲霉素和高脂饮食喂养（STAM™模型）诱导小鼠患上NASH。通过在耳部局部涂抹免疫调节剂（IMQ）诱导小鼠患上银屑病。使用组织学分析确定肝损伤和银屑病皮肤变化的严重程度。使用定量PCR分析评估皮肤组织中的基因表达。使用酶联免疫吸附法确定血清细胞因子水平。为了检测正常人表皮角质细胞（NHEKs）的固有免疫反应，我们给予细胞白细胞介素（IL）-17A，肿瘤坏死因子（TNF）-α和AdipoRon，即脂联素受体激动剂。NASH小鼠与患有银屑病的NASH小鼠之间的肝组织损伤程度（脂肪沉积、炎症和纤维化）无差异。相反，NASH与银屑病同时存在显著增加了银屑病小鼠的皮肤变化，如表皮增生。炎性细胞因子在银屑病小鼠的发炎皮肤中表达，并且基因表达，尤其是Il23a，Il1b，Il36g和Mip2的表达，通过NASH的共同存在而显著上调。角质细胞活化标志物基因Defb4b和Krt16的表达也通过NASH的共同存在而上调。与不患NASH的小鼠相比，同时患有NASH和银屑病的小鼠血清TNF-α和IL-17水平升高，NASH小鼠的血清脂联素水平降低。在NHEK的培养中，TNF-α和IL-17A协同上调CXCL1、CXCL8和IL1B的表达。AdipoRon治疗抑制了上调的炎性基因表达，反映了脂联素的抗炎能力。NASH的共同存在加剧了银屑病与血清炎症性细胞因子水平增加和血清脂联素水平降低相关的皮肤变化。结合体外发现，增加的炎性细胞因子水平和降低的脂联素水平可能促进银屑病皮损中表皮角质细胞的固有免疫反应。总的来说，在临床实践中，针对共同存在的NASH进行治疗干预对于实现银屑病有利的预后至关重要。版权所有 © 2023 Takezaki、Morizane、Ikeda、Iseki、Sakamoto、Kawakami、Hashiguchi、Shirakata、Nishina和Mukai。

Clinical studies have suggested a bidirectional association between non-alcoholic steatohepatitis (NASH) and psoriasis, affecting each other's development and severity. Here, we explored bidirectional causal linkages between NASH and psoriasis using a murine model.NASH was induced in mice by streptozotocin injection at 2 days of age and by high-fat diet feeding (STAM™ model). Psoriasis was induced by topical application of imiquimod (IMQ) on the ear. The severities of liver damage and psoriatic skin changes were determined using histological analysis. Gene expression in the skin tissues was evaluated using quantitative PCR analysis. Serum cytokine levels were determined using enzyme-linked immunosorbent assay. To examine the innate immune responses of normal human epidermal keratinocytes (NHEKs), the cells were treated with interleukin (IL)-17A, tumor necrosis factor (TNF)-α, and AdipoRon, an adiponectin receptor agonist.There were no differences in the degree of liver tissue damage (fat deposition, inflammation, and fibrosis) between NASH mice with and those without psoriasis. Conversely, the co-occurrence of NASH significantly augmented psoriatic skin changes, represented by epidermal hyperplasia, in psoriatic mice. Pro-inflammatory cytokines were expressed in the inflamed skin of psoriatic mice, and the expression of genes, especially Il23a, Il1b, Il36g, and Mip2, was significantly upregulated by the co-occurrence of NASH. The expression of keratinocyte activation marker genes Defb4b and Krt16 was also upregulated by the co-occurrence of NASH. The serum TNF-α and IL-17 levels were increased by the co-occurrence of NASH and psoriasis. The serum adiponectin levels decreased in NASH mice compared with that in non-NASH mice. In NHEK culture, TNF-α and IL-17A synergistically upregulated CXCL1, CXCL8, and IL1B expression. The upregulated pro-inflammatory gene expression was suppressed by AdipoRon treatment, reflecting the anti-inflammatory capacity of adiponectin.The co-occurrence of NASH exacerbated psoriatic skin changes associated with increased serum inflammatory cytokine levels and decreased serum adiponectin levels. Combined with in vitro findings, increased inflammatory cytokine levels and decreased adiponectin levels likely promote innate immune responses in epidermal keratinocytes in psoriatic skin lesions. Overall, therapeutic intervention for co-occurring NASH is essential to achieve a favorable prognosis of psoriasis in clinical practice.Copyright © 2023 Takezaki, Morizane, Ikeda, Iseki, Sakamoto, Kawakami, Hashiguchi, Shirakata, Nishina and Mukai.