探討gamma-胺基丁酸對Imiquimod誘發乾癬小鼠免疫調節之影響

Abstract

乾癬 (Psoriasis) 為一種由免疫失衡引發的慢性皮膚發炎疾病，且經常合併關節炎的發生，影響著全球2-3%的人口。已知gamma-胺基丁酸(Gamma-aminobutyric acid, GABA) 為一種抑制型神經傳導物質，也具有抗發炎和調節免疫的功能。在乾癬患者及乾癬動物模式中皆觀察到體內GABA含量降低，且有憂鬱的情況。因此，本研究欲利用可誘發乾癬的Imiquimod (IMQ) 建立乾癬小鼠模式，探討GABA對於乾癬病情及免疫調節的影響。實驗方法為將8週齡C57BL/6J小鼠分為四組：控制組 (Ctrl)、IMQ誘發組 (IMQ)、IMQ誘發GABA補充組 (GABA/IMQ) 和IMQ誘發Dex藥物組 (Dex/IMQ)， GABA/IMQ組是餵予含500 kg/diet GABA純物質的飼料，其餘組別餵予AIN-93飼料，在第三次誘發前一週改以管餵方式給予GABA。在12週齡、20週齡以及26週齡時，分別在小鼠背部和耳朵塗抹62.5 mg和10 mg的IMQ誘發乾癬，連續塗抹5天。在第三次誘發塗抹5天共餵食18週後犧牲。結果顯示，IMQ誘發可使皮膚出現紅腫、皮屑和皮膚增厚等乾癬病徵，以及皮膚IL-17、IL-23、TNF-α和IL-10的含量上升。補充GABA可顯著降低IMQ誘導造成的背部皮膚增厚，以及IL-17的生成量。脾臟免疫分析結果顯示，IMQ也會促進脾臟細胞IL-17的分泌量，降低TNF-α、IL-6和IL-10的分泌量，但是補充GABA對於脾臟的細胞激素分泌無顯著影響。綜合上述，補充GABA可以藉由調節皮膚組織IL-17的表現量，顯著降低背部皮膚的增厚程度，具有減緩乾癬病情的潛力。

Psoriasis is a common chronic immune-induced inflammatory skin disease, accompanied by complications such as arthritis, and affects 2-3% of the world's population. Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter, GABA also has anti-inflammatory and immune-regulating functions. In psoriasis patients and animal models, GABA levels were reduced, and depression. Therefore, we established an IMQ-induced psoriasis-like dermatitis mice model to explore the immunomodulatory effect of GABA on psoriasis mice. The eight-week-old mice were divided into four groups: Ctrl group, IMQ group, GABA/IMQ group, and Dex/IMQ group. The GABA/IMQ group was fed an AIN-93 diet containing 500 kg/diet GABA pure compound, and the other groups were fed an AIN-93 diet, GABA was given by oral gavage one week before the third induction. IMQ was applied to the back and ear of mice for 5 days to induce psoriasis at 4 weeks, 12 weeks, and 18 weeks, respectively, and sacrificed after the third induction with 18 weeks GABA supplement. The result demonstrated that IMQ induction can cause psoriasis symptoms such as erythema, scales, and thickness on the skin, increased the production of IL-17, IL-23, TNF-α, and IL-10. Back skin thickness and IL-17 production were decreased by GABA supplement. In the spleen, IMQ induction increased IL-17 secretion and decreased the secretion of TNF-α, IL-6, and IL-10. However, the levels cytokine did not show any significant difference between the GABA/IMQ group and IMQ group, showing that GABA might alleviate psoriasis by affecting the immune response in local skin rather than in peripheral immune organs.In summary, GABA alleviated skin thicknesses by regulating skin IL-17 production in the IMQ-induced psoriasis-like dermatitis mice model, which has the potential to decrease the disease degree of psoriasis.