Cutaneous Liver X Receptor Activation Prevents the Formation of Imiquimod-Induced Psoriatic Dermatitis.
Cutaneous Liver X Receptor Activation Prevents the Formation of Imiquimod-Induced Psoriatic Dermatitis.
复制标题
皮肤肝脏 X 受体激活可预防咪喹莫特诱发的银屑病皮炎的形成。
DOI：
10.1016/j.jid.2021.08.432
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发表时间：
2021
影响因子：
6.5
通讯作者：
Kabashima K.
中科院分区：
文献类型：
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作者：
Otsuka M.;Egawa G.;Dainichi T.;Okuno T.;Ishida Y.;Chow Z.;Asahina R.;Miyake T.;Nomura T.;Kitoh A.;Yokomizo T.;Kabashima K.
银屑病是一种以角质形成细胞(KC)过度增殖为特征的慢性炎症性皮肤病(Nestle等人，2009年)。近年来，银屑病被认为是一种与多器官异常和血脂异常相关的免疫代谢疾病(Sterry et al.，2007)；然而，皮肤中脂代谢的失调是否影响银屑病的发病机制尚不清楚。肝X受体(LXR)是一种核受体，由两种亚型组成：LXRα(NR1H3)和LXRβ(NR1H2)(Chawla等人，2001年)，这两种亚型是胆固醇的重要调节因子(Schulman，2017)。先前的研究表明，局部应用LXR激动剂可以抑制接触性皮炎的发展(Fowler等人，2003年)，并且LXRα在银屑病皮损的KC中的表达受到抑制(Gupta等人，2010年)。在这项研究中，我们通过在咪喹莫特(Imiquimod)诱导的银屑病小鼠模型上局部应用合成的LXR激动剂GW3965来研究LXR信号在银屑病中的作用。我们局部应用10 mM的GW3965或乙醇作为载体对照，并联合ImQ连续7天。与人类银屑病的情况类似，ImQ治疗的皮肤中LXR的表达水平低于对照皮肤(补充图S1)。GW3965治疗组小鼠的IMQ引起的耳肿胀和表皮增生比对照组小鼠轻微(图1a和b)。我们在第3天和第5天用流式细胞仪检测免疫细胞的渗透，发现在第3天，赋形剂处理的皮肤的中性粒细胞数量是GW3965处理的皮肤的2.5倍，但其他免疫细胞的数量在GW3965处理的皮肤和对照皮肤中相似(图1c)。中性粒细胞趋化因子(CXCL1、CxCL2和CCL20)和银屑病相关基因(Il1a、Il1b、Il23a和IL17a)的mRNA表达水平在GW3965治疗组中较低(图1d)，与第3天皮损中中性粒细胞数量的减少一致(图1c)。相比之下，无论同时进行ImQ处理，LXR反应基因ABCA1的表达水平在GW3965处理的皮肤中都显著高于对照组，这表明LXR在皮肤中处于激活状态(图1d)。检测中性粒细胞活化标志物CXCR4和CD49b的表达水平，并检测瓜氨酸组蛋白H3阳性细胞的百分率，以检查网织分裂活性。在GW3965和赋形剂处理组之间，这些标志物的表达没有显著差异(数据未显示)，表明中性粒细胞功能不受LXR激活的影响。综上所述，这些结果表明，在ImQ诱导的银屑病模型中，皮肤应用LXR激动剂在早期阶段减少了中性粒细胞的募集，并导致了钝性皮肤炎症。
Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte (KC) hyperproliferation (Nestle et al., 2009). In recent years, psoriasis is recognized as an immunometabolic disease associate with multiorgan abnormalities and dyslipidemia (Sterry et al., 2007); however, it remains unclear whether the dysregulation of lipid metabolism in the skin affects the pathogenesis of psoriasis. Liver X receptor (LXR) is a nuclear receptor composed of two isoforms: LXRα (NR1H3) and LXRβ (NR1H2)(Chawla et al., 2001), which are important regulators of cholesterol (Schulman, 2017). Previous studies showed that the topical application of LXR agonists inhibits the development of contact dermatitis (Fowler et al., 2003) and that LXRα expression is suppressed in KCs in psoriatic lesions (Gupta et al., 2010). In this study, we investigated the role of LXR signaling in psoriasis through topical application of a synthetic LXR agonist, GW3965, in an imiquimod (IMQ)-induced psoriatic murine model.We topically applied the LXR agonist 10 mM of GW3965 or ethanol as vehicle control in combination with IMQ for 7 consecutive days. Analogous to the human psoriasis condition, LXR expression levels were lower in the IMQ-treated skin than in the control skin (Supplementary Figure S1). IMQ-induced ear swelling and epidermal hyperplasia were milder in mice treated with GW3965 than in the control mice (Figure 1 a and b). We evaluated immune cell infiltration by flow cytometry on days 3 and 5 and found that the numbers of neutrophils were 2.5-fold higher in the vehicle-treated skin than in the GW3965-treated skin on day 3, but the numbers of other immune cells were comparable between the GW3965-treaded skin and control skin (Figure 1 c). The mRNA expression levels of neutrophil chemoattractants (Cxcl1, Cxcl2, and Ccl20) and psoriasis-related genes (Il1a, Il1b, Il23a, and Il17a) were lower in the GW3965-treated group (Figure 1 d), consistent with the lower numbers of neutrophils in the lesional skin on day 3 (Figure 1 c). In contrast, the expression levels of LXR response gene Abca1 were significantly higher in the GW3965-treated skin regardless of simultaneous IMQ treatment, showing LXR activation in the skin (Figure 1 d). We also evaluated the expression levels of neutrophil activation markers such as CXCR4 and CD49b and examined the percentage of citrullinated histone H3‒positive cells to check the netosis activity. No significant difference was observed in the expression of these markers between the GW3965-and the vehicle-treated group (data not shown), suggesting that neutrophil function is not influenced by LXR activation. Taken together, these results suggest that cutaneous application of the LXR agonist attenuated neutrophil recruitment in the early phase and led to blunted skin inflammation in IMQ-induced psoriatic model.