The skin microbiome in acne

项目总结/摘要 痤疮是一种毛囊皮脂腺单位（PSebU）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。的主要 PSebU的微生物组中的细菌物种是痤疮丙酸杆菌（又名痤疮皮肤杆菌）， 会引发炎症的唾液。该提案旨在了解为什么痤疮丙酸杆菌促进 痤疮患者的毛囊皮脂腺单位（PSebU）中只有一部分存在炎症，而其他人则存在炎症。 没有疾病。为了解决这一人类重大疾病的核心问题， 理解howP。痤疮与宿主免疫反应相互作用，我们将研究疾病相关的 与不促进疾病的其他菌株（PH-健康皮肤）相比，PA-痤疮相关 这项建议的目的是基于最近的几项重要发现， 阐明痤疮丙酸杆菌和PSebU环境如何促进炎症。PA显示优先 诱导促炎细胞因子IFN-γ和IL-17，而PH诱导抗炎细胞因子IL-10。 外周血单个核细胞（PBMC）。补充这一点，我们还发现，当痤疮丙酸杆菌， 置于模拟痤疮堵塞PSebU的厌氧环境条件下，它们然后产生 短链脂肪酸（SCFA）促进角质形成细胞（KC）释放细胞因子。这是由于 某些痤疮丙酸杆菌菌株诱导表观遗传学改变的能力， 配体。因此，在本提案中，我们将联合收割机共同努力，精确地确定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 痤疮微生物组可以促进淋巴和淋巴细胞中的促炎反应与抗炎反应的机制 骨髓细胞，2）了解痤疮微生物组的代谢物诱导细胞因子的机制 KC和皮脂腺细胞中的反应;以及3）确定皮肤微生物组的菌株特异性成员如何 调节皮肤炎症。拟议的研究将为皮肤微生物组如何 塑造皮肤免疫反应，导致炎症与稳态，具有潜在的 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.