The skin microbiome in acne

项目摘要/摘要 痤疮是毛发皮脂素单位(PSebU)的一种疾病，在慢性皮肤病中排名第三 造成残疾，是心理损伤和医疗费用的主要原因。占优势的 在PSebU的微生物群中的细菌种类是痤疮丙酸杆菌(又名痤疮皮肤杆菌)，一种 会引发炎症的共生关系。这项提案试图理解为什么P.acnes促进 痤疮患者中只有部分毛囊皮脂腺单位(PSebU)有炎症反应，而其他人则有 不是得了病。解决这一人类重大疾病的中心问题，推进根本 对HOW的理解。与宿主免疫反应相互作用，我们将研究与疾病相关的 与其他不会导致疾病的菌株(PH-健康皮肤)的比较(与PA-痤疮相关) 这项提议的目的是基于最近的几项重要发现，这些发现带来了新的 关于巴氏杆菌和PSebU环境如何促进炎症。PAIS显示优先考虑 诱导促炎细胞因子干扰素-γ和IL-17，而诱导抗炎细胞因子IL-10in 外周血单核细胞(PBMC)。补充这一点，我们还发现当P. 将它们置于厌氧环境条件下，模拟堵塞的粉刺PSebU，然后产生 促进角质形成细胞释放细胞因子的短链脂肪酸(SCFA)。发生这种情况是由于 某些痤疮假单胞菌诱导表观遗传改变打破KC对TLR免疫耐受的能力 配基。因此，在这项提案中，我们将联合我们的努力，准确地界定P。 痤疮在PSebU中诱导炎症，并促进疾病。我们的具体目标是：1)确定 痤疮微生物群促进淋巴和组织中促炎症反应的机制 髓系细胞，2)了解痤疮微生物组代谢产物诱导细胞因子的机制 KCs和皮脂细胞的反应；以及3)决定皮肤微生物组特定菌株成员的方式 调节皮肤炎症。这项拟议的研究将为我们提供关于皮肤微生物群如何 塑造导致炎症和动态平衡的皮肤免疫反应，有可能 对皮肤病的干预。

PROJECT SUMMARY/ABSTRACT Acne is a disease of the pilosebaceous unit (PSebU) that is ranked third among chronic skin diseases for causing disabilityand is a major cause of psychological impairment and medical expense. The predominant bacterial species in the microbiome of the PSebU is Propionibacterium acnes (aka Cutibacterium acnes), a commensal that can trigger inflammation. This proposal seeks to understand why P. acnespromotes inflammation in only some of the pilosebaceous unit (PSebU) of individuals with acne,yet other individuals do not have disease. To solve this central question of this major human disease and advance fundamental understanding of howP. acnesinteracts with the host immune response, we will study disease-associated phylotypes (PA- acne associated) compared to other strains that do not promote disease (PH- healthy skin associated).The aims of this proposal are based on several important recent discoveries that have shed new light on how P. acnesand the PSebU environment can promote inflammation. PAis shown to preferentially induce pro-inflammatory cytokines IFN-γ and IL-17 whereas PHinduces the anti-inflammatory cytokine IL-10in peripheral blood mononuclear cells (PBMC).Complementing this, we have also found that thatwhen P. acnesis placed under anerobic environmental conditions that mimic the plugged PSebU of acne, they then produce short chain fatty acids (SCFAs) that promote cytokine release from keratinocytes (KC). This occurs due to the capacity of some P. acnes strains toinduce epigenetic changes that break immune tolerance of KC to TLR ligands. In this proposal, we will therefore combine our efforts to precisely define mechanisms by which P. acnesinduces inflammation in the PSebU and promotes disease. Our specific aims are: 1) Determine the mechanisms by which the acne microbiome can promote pro- vs. anti-inflammatory responses in lymphoid and myeloid cells, 2) Understand the mechanisms by which metabolites of the acne microbiome induce cytokine responses in KCs and sebocytes; and 3) Determine how strain-specific members of the skin microbiome regulate cutaneous inflammation. The proposed studies will provide new insight into how the skin microbiome shapes cutaneous immune responses leading to inflammation vs. homeostasis, with the potential for intervention in skin disease.