Chitinase-3-like-1 (CHI3L1) is known to induce inflammation in the progression of allergic diseases. Previous our studies revealed that 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111; K284), the CHI3L1 inhibiting compound, has the anti-inflammatory effect on neuroinflammation. In this study, we investigated that K284 treatment could inhibit the development of atopic dermatitis (AD). To identify the effect of K284, we used phthalic anhydride (5% PA)-induced AD animal model and in vitro reconstructed human skin model. We analyzed the expression of AD-related cytokine mediators and NF-κB signaling by Western blotting, ELISA and quantitative real-time PCR. Histological analysis showed that K284 treatment suppressed PA-induced epidermal thickening and infiltration of mast cells. K284 treatment also reduced PA-induced release of inflammatory cytokines. In addition, K284 treatment inhibited the expression of NF-κB activity in PA-treated skin tissues and TNF-α and IFN-γ-treated HaCaT cells. Protein-association network analysis indicated that CHI3L1 is associated with lactoferrin (LTF). LTF was elevated in PA-treated skin tissues and TNF-α and IFN-γ-induced HaCaT cells. However, this expression was reduced by K284 treatment. Knockdown of LTF decreased the expression of inflammatory cytokines in TNF-α and IFN-γ-induced HaCaT cells. Moreover, anti-LTF antibody treatment alleviated AD development in PA-induced AD model. Our data demonstrate that CHI3L1 targeting K284 reduces AD-like skin inflammation and K284 could be a promising therapeutic agent for AD by inhibition of LTF expression.

中文翻译：

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K284-6111 对 Chitinase-3-like-1 的抑制可通过抑制乳铁蛋白来减少特应性皮肤炎症。


已知 Chitinase-3-like-1 (CHI3L1) 会在过敏性疾病的进展过程中诱导炎症。我们之前的研究表明，2-({3-[2-(1-环己烯-1-基)乙基]-6,7-二甲氧基-4-氧代-3,4-二氢-2-喹唑啉基}硫基)-N -(4-乙基苯基)丁酰胺 (K284-6111; K284) 是一种 CHI3L1 抑制化合物，对神经炎症具有抗炎作用。在这项研究中，我们研究了 K284 治疗可以抑制特应性皮炎 (AD) 的发展。为了确定 K284 的作用，我们使用邻苯二甲酸酐 (5% PA) 诱导的 AD 动物模型和体外重建的人类皮肤模型。我们通过蛋白质印迹、ELISA 和实时定量 PCR 分析了 AD 相关细胞因子介质和 NF-κB 信号传导的表达。组织学分析表明，K284 治疗抑制了 PA 诱导的表皮增厚和肥大细胞浸润。 K284 治疗还减少了 PA 诱导的炎症细胞因子的释放。此外，K284 处理抑制 PA 处理的皮肤组织以及 TNF-α 和 IFN-γ 处理的 HaCaT 细胞中 NF-κB 活性的表达。蛋白质关联网络分析表明 CHI3L1 与乳铁蛋白 (LTF) 相关。 PA 处理的皮肤组织以及 TNF-α 和 IFN-γ 诱导的 HaCaT 细胞中 LTF 升高。然而，K284 处理降低了该表达。 LTF 的敲低降低了 TNF-α 和 IFN-γ 诱导的 HaCaT 细胞中炎症细胞因子的表达。此外，抗 LTF 抗体治疗可减轻 PA 诱导的 AD 模型中 AD 的发展。我们的数据表明，靶向 K284 的 CHI3L1 可减少 AD 样皮肤炎症，并且 K284 可能通过抑制 LTF 表达而成为 AD 的有前途的治疗剂。