Department of Dermatology, University of California, San Diego, La Jolla, CA 92093; and.
Department of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, 06847 Dessau, Germany.
J Immunol. 2019 Mar 15;202(6):1767-1776. doi: 10.4049/jimmunol.1800893. Epub 2019 Feb 8.
The regulation of cutaneous inflammatory processes is essential for the human skin to maintain homeostasis in the presence of the dense communities of resident microbes that normally populate this organ. Forming the hair follicle-associated sebaceous gland, sebocytes are specialized lipid-producing cells that can release inflammatory mediators. Cytokine and chemokine expression by pilosebaceous epithelial cells (i.e., sebocytes and follicular keratinocytes) has been proposed to contribute to the common human skin disease acne vulgaris. The underlying mechanisms that drive inflammatory gene expression in acne-involved pilosebaceous epithelial cells are still unknown because almost all sebaceous follicles contain dense concentrations of bacteria yet only some show an inflammatory reaction. In this study, we hypothesized that metabolites from the abundant skin-resident microbe can influence cytokine expression from human sebocytes. We show that short-chain fatty acids produced by under environmental conditions that favor fermentation will drive inflammatory gene expression from sebocytes. These molecules are shown to influence sebocyte behavior through two distinct mechanisms: the inhibition of histone deacetylase (HDAC) activity and the activation of fatty acid receptors. Depletion of HDAC8 and HDAC9 in human sebocytes resulted in an enhanced cytokine response to TLR-2 activation that resembled the transcriptional profile of an acne lesion. These data provide a new insight into the regulation of inflammatory gene expression in the skin, further characterize the contribution of sebocytes to epidermal immunity, and demonstrate how changes in the metabolic state of the skin microbiome can promote inflammatory acne.
皮肤炎症过程的调节对于人类皮肤在密集的常驻微生物群落存在的情况下维持内稳态至关重要，这些常驻微生物通常存在于该器官中。形成毛囊相关的皮脂腺，皮脂腺是专门的脂质产生细胞，可释放炎症介质。有研究提出，毛发皮脂腺上皮细胞（即皮脂腺细胞和毛囊角质形成细胞）中的细胞因子和趋化因子表达有助于常见的人类皮肤病痤疮的发生。导致参与痤疮的毛发皮脂腺上皮细胞中炎症基因表达的潜在机制尚不清楚，因为几乎所有的皮脂腺滤泡都含有密集的细菌浓度，但只有一些会发生炎症反应。在这项研究中，我们假设丰富的皮肤常驻微生物的代谢产物可以影响人类皮脂腺细胞中的细胞因子表达。我们表明，在有利于发酵的环境条件下产生的短链脂肪酸会促进皮脂腺细胞中炎症基因的表达。这些分子通过两种不同的机制影响皮脂腺细胞的行为：抑制组蛋白去乙酰化酶（HDAC）活性和激活脂肪酸受体。在人类皮脂腺细胞中耗尽 HDAC8 和 HDAC9 会导致对 TLR-2 激活的细胞因子反应增强，类似于痤疮病变的转录谱。这些数据为皮肤中炎症基因表达的调节提供了新的见解，进一步描述了皮脂腺细胞对表皮免疫的贡献，并展示了皮肤微生物组代谢状态的变化如何促进炎症性痤疮的发生。
