Chen Wenfang, Ge Lingzhi, Zhang Chao
Department of Dermatovenereology, The Second Affiliated Hospital of Shandong First Medical University, No.366 Taishan Street, Taian, 271000, China.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr;398(4):3843-3859. doi: 10.1007/s00210-024-03461-5. Epub 2024 Oct 4.
Berberine (BBR), a Rhizoma Coptis-sourced isoquinoline alkaloid, is an effective drug for psoriasis treatment with its therapeutic mechanism remaining unclear. We delved into the mechanism of BBR affecting psoriatic skin inflammation by regulating keratinocyte pyroptosis. A psoriasis-like skin inflammation mouse model was induced by imiquimod (IMQ) and treated with BBR and a p38 activator anisomycin. Human epidermal keratinocytes (HEKs) were stimulated with five chemokines (M5) [interleukin (IL)-17A, IL-22A, oncostatin M, tumor necrosis factor-α, IL-1α] to simulate psoriasis immune microenvironment, then treated with BBR and anisomycin. Psoriasis skin lesions, skin tissue damage, cell viability and death, and gasdermin D-N (GSDMD-N) and NOD-like receptor protein 3 (NLRP3) positive cell numbers were assessed. The p38 mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) pathway and levels of the NLRP3/GSDMD pathway-related proteins and inflammatory factors were determined. BBR alleviated M5-induced HEK pyroptosis by inactivating NLRP3 inflammasomes. BBR inhibited the p38 MAPK/NF-κB pathway, and its effects on HEKs were partly averted by activating the p38 MAPK/NF-κB pathway. BBR repressed NLRP3 inflammasome activation and pyroptosis by inhibiting the p38 MAPK/NF-κB pathway. Collectively, BBR suppressed keratinocyte NLRP3/GSDMD pathway pyroptosis by suppressing the p38 MAPK/NF-κB pathway, thereby affecting psoriasis skin inflammation.
黄连素（BBR）是一种从黄连中提取的异喹啉生物碱，是治疗银屑病的有效药物，但其治疗机制尚不清楚。我们深入研究了BBR通过调节角质形成细胞焦亡影响银屑病皮肤炎症的机制。用咪喹莫特（IMQ）诱导建立银屑病样皮肤炎症小鼠模型，并用BBR和p38激活剂茴香霉素进行治疗。用五种趋化因子（M5）[白细胞介素（IL）-17A、IL-22A、抑瘤素M、肿瘤坏死因子-α、IL-1α]刺激人表皮角质形成细胞（HEK）以模拟银屑病免疫微环境，然后用BBR和茴香霉素进行处理。评估银屑病皮肤病变、皮肤组织损伤、细胞活力和死亡情况，以及gasdermin D-N（GSDMD-N）和NOD样受体蛋白3（NLRP3）阳性细胞数量。测定p38丝裂原活化蛋白激酶（MAPK）/核因子-κB（NF-κB）信号通路以及NLRP3/GSDMD信号通路相关蛋白和炎症因子的水平。BBR通过使NLRP3炎性小体失活减轻M5诱导的HEK焦亡。BBR抑制p38 MAPK/NF-κB信号通路，而激活p38 MAPK/NF-κB信号通路可部分逆转其对HEK的作用。BBR通过抑制p38 MAPK/NF-κB信号通路抑制NLRP3炎性小体活化和焦亡。总体而言，BBR通过抑制p38 MAPK/NF-κB信号通路抑制角质形成细胞NLRP3/GSDMD信号通路焦亡，从而影响银屑病皮肤炎症。
