半乳糖凝集素-12透過皮脂腺調節皮膚之免疫反應

Abstract

皮脂腺是一種全分泌腺腺體，其主要功能是分泌以油脂為主體的皮脂，維持皮膚的屏障功能。脂質產生調節失常會導致部分皮膚疾病，特別是以皮膚乾燥龜裂為特徵的異位性皮膚炎的惡化。儘管，在脂質的生合成上，皮脂腺已有相當充分的研究，但鮮少有研究評估皮脂腺在皮膚免疫反應中的作用。而在本篇研究中，我們發現皮脂腺和皮脂細胞表達介白素（Interleukin，IL）-4受體，並在接受介白素-4刺激後產生大量的Th2相關促發炎介質，表明皮脂腺具有免疫調節的作用。半乳糖凝集素(Galectin)-12是在皮脂腺細胞中表達的脂肪生成因子，同時也影響了皮脂腺的分化和增殖。透過抑制皮脂細胞的半乳糖凝集素-12表達，我們發現半乳糖凝集素-12調節了細胞暴露於介白素-4時的免疫反應，並透過上調過氧化物酶體增殖物活化受體-γ (Peroxisome Proliferator Activated Receptors-γ，PPARγ)來促使趨化激素-CCL26表達。此外，半乳糖凝集素-12還抑制內質網壓力反應(Endoplasmic reticulum stress，ER stress)因子的表達，當使用藥物誘發皮脂腺細胞中的內質網壓力反應時，介白素-4引發的CCL26表現遭到抑制，這表明半乳糖凝集素-12抑制了內質網壓力反應來維持介白素-4相關的信號傳遞。我們也使用半乳糖凝集素-12敲除小鼠證實，半乳糖凝集素-12維持了介白素-4誘導的皮脂腺肥大和皮膚炎的發展。因此，我們認為半乳糖凝集素-12通過調節皮脂腺內的氧化物酶體增殖物活化受體-γ表達和內質網壓力反應來調節皮膚免疫反應。

Sebaceous glands are holocrine glands that produce sebum, which primarily contains lipids that help maintain the barrier function of the skin. Dysregulated lipid production contributes to the progression of some diseases characterized by dry skin, including atopic dermatitis. Although the lipid production of sebaceous glands has been well studied, few studies have assessed their role in skin immune responses. We found that sebaceous glands and sebocytes expressed interleukin (IL)-4 receptor and produced high levels of Th2-associated inflammatory mediators following IL-4 treatment, suggesting immunomodulatory effects. Galectin-12 is a lipogenic factor expressed in sebocytes that affects their differentiation and proliferation. Using galectin-12-knockdown sebocytes, we demonstrated that galectin-12 regulated the immune response in cells exposed to IL-4 and promoted CCL26 expression by upregulating PPARγ. Moreover, galectin-12 suppresses the expression of endoplasmic reticulum (ER) stress-response molecules and CCL26 upregulation by IL-4 was reversed following sebocyte treatment with inducers of ER stress, suggesting that galectin-12 controls IL-4 signaling by suppressing ER stress. Using galectin-12-knockout mice, we demonstrated that galectin-12 positively regulated the IL-4-induced enlargement of the sebaceous glands and the development of an atopic dermatitis-like phenotype. Thus, galectin-12 regulates the skin immune response through PPARγ expression and ER events within sebaceous glands.