Department of Dermatology, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei City, 10449, Taiwan; Department of Medicine, MacKay Medical College, No.46, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, 25245, Taiwan.
Department of Dermatology, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N. Rd., Taipei City, 10449, Taiwan; MacKay Junior College of Medicine, Nursing, and Management, No. 42, Sec. 3, Zhongzheng Rd., Sanzhi Dist., New Taipei City, 25245, Taiwan.
Free Radic Biol Med. 2022 Feb 20;180:121-133. doi: 10.1016/j.freeradbiomed.2022.01.004. Epub 2022 Jan 7.
UVB can induce inflammatory responses contributing to diverse skin damage. UVB-triggered inflammasome activation of human keratinocytes underlies UVB-induced skin sunburn reaction. Pleiotropic functions of spleen tyrosine kinase (Syk) have rendered it as a potential therapeutic target. In immunocytes, Syk modulates immunoreceptor signaling and NLRP3 inflammasome activation. In skin, Syk mediates EGFR signaling, regulates keratinocyte differentiation and is involved in inflammatory disorders. However, roles of Syk in UVB-induced inflammasome activation in keratinocytes remain elusive. We investigated roles of keratinocyte Syk in UVB-triggered photo-responses. Primary normal human epidermal keratinocytes (NHEKs) isolated from skin were used. Syk knockdown or Syk inhibitor R406 was applied to investigate functions of keratinocyte Syk in UVB photobiology. The possible in vivo role of Syk was evaluated by checking UVB-induced skin damage in R406-treated mice. UVB was able to induce Syk phosphorylation in NHEKs that could be regulated by reactive oxygen species (ROS) generation and EGFR. Syk knockdown or Syk inhibitor (R406) treatment reduced UVB-triggered apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) crosslinking, procaspase-1 cleavage, active IL-1β formation, and gasdermin D activation, indicating roles of Syk in UVB-triggered inflammasome activation in keratinocytes. UVB-induced production of IL-8, TNF-α, ROS, and phosphorylation of JNK and p38 were attenuated after Syk knockdown or inhibition. R406 ameliorated UVB-induced mouse skin damage, including erythema and transepidermal water loss (TEWL). Thus, Syk participated in UVB-induced inflammasome activation and inflammatory response in vitro and in vivo, suggesting potential photo-protective effects of Syk inhibition in UVB-induced skin inflammation.
UVB 可诱导炎症反应，导致多种皮肤损伤。UVB 触发人类角质形成细胞中的炎性体激活是 UVB 诱导皮肤晒伤反应的基础。脾酪氨酸激酶 (Syk) 的多效性功能使其成为潜在的治疗靶点。在免疫细胞中，Syk 调节免疫受体信号和 NLRP3 炎性体激活。在皮肤中，Syk 介导 EGFR 信号转导，调节角质形成细胞分化，并参与炎症性疾病。然而，Syk 在角质形成细胞中 UVB 诱导的炎性体激活中的作用仍不清楚。我们研究了角质形成细胞 Syk 在 UVB 触发的光反应中的作用。使用从皮肤中分离的原代正常人表皮角质形成细胞 (NHEK)。应用 Syk 敲低或 Syk 抑制剂 R406 研究角质形成细胞 Syk 在 UVB 光生物学中的作用。通过检查 R406 处理小鼠的 UVB 诱导的皮肤损伤来评估 Syk 的可能体内作用。UVB 能够诱导 NHEK 中的 Syk 磷酸化，这可以通过活性氧 (ROS) 生成和 EGFR 调节。Syk 敲低或 Syk 抑制剂 (R406) 处理减少了 UVB 触发的凋亡相关斑点样蛋白包含半胱氨酸天冬氨酸蛋白酶募集域 (ASC) 交联、半胱天冬酶-1 切割、活性 IL-1β 形成和 Gasdermin D 激活，表明 Syk 在角质形成细胞中 UVB 触发的炎性体激活中的作用。Syk 敲低或抑制后，UVB 诱导的 IL-8、TNF-α、ROS 的产生和 JNK 和 p38 的磷酸化减少。R406 改善了 UVB 诱导的小鼠皮肤损伤，包括红斑和经表皮水分流失 (TEWL)。因此，Syk 在体外和体内参与了 UVB 诱导的炎性体激活和炎症反应，表明 Syk 抑制在 UVB 诱导的皮肤炎症中具有潜在的光保护作用。
