Microbiota Control Lung Th17 Cell Response and Plasticity Leading to Autoimmune Lung Disease

微生物群控制肺 Th17 细胞反应和可塑性导致自身免疫性肺病

基本信息

批准号：
10052963
负责人：
Hsin-Jung Joyce Wu
金额：
$ 44.42万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10052963
关键词：
Address Area Arthritis Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity Bacteria CCL20 gene CCR6 gene CD4 Positive T Lymphocytes Cause of Death Cell Communication Cell Differentiation process Cells Data Development Disease Dissection Epithelial Epithelial Cells Epithelium Equilibrium Etiology FOXP3 gene Face Fostering Future Glycolysis Homing Human Hypoxia Hypoxia Inducible Factor In Situ Industrialization Interleukin-17 K/BxN model Lesion Ligands Lung Lung diseases Measures Mediating Methods Microbe Microscopic Modeling Mus Pathogenesis Patients Pharmaceutical Preparations Phase Phenotype Physiological Pimonidazole Population Production Public Health Reporting Rheumatoid Arthritis Role Signal Transduction Site T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Testing Tissues alveolar epithelium arthropathies autoimmune arthritis base cell type combat commensal bacteria design dysbiosis follow-up gut bacteria gut microbiota gut-lung axis hexokinase inhibitor/antagonist lung microbiota lymphoid structures microbiota migration outcome forecast pathobiont recombinase-mediated cassette exchange recruit remote control response sensor systemic autoimmune disease tissue culture

项目摘要

Project Summary. Lung complications are a common and major cause of death in patients with rheumatoid arthritis (RA). Therapies are limited, and arthritis modulating drugs can actually worsen lung disease in RA patients, yet little is known regarding RA-related lung pathogenesis. It is evident that the gut and gut microbiota have a strong influence in many lung diseases. Mechanistically, this phenomenon known as the gut-lung axis, is poorly defined. We reported that through gut-lung communication, a gut commensal, segmented filamentous bacteria (SFB) are able to expand dual T cell receptor (TCR)-expressing T helper 17 (Th17) cells, leading to lung tertiary lymphoid structures (TLS), lesions often associated with poor prognosis in autoimmune patients. To understand gut-lung axis, we propose addressing the mechanisms utilized by SFB to promote a Th17 cell response, gut-lung migration, and lung TLS formation. Hypoxia-inducible factor-1α (HIF-1α) senses O2 in hypoxic tissues, e.g. the gut and inflamed tissues, and is known to enhance glycolysis and promote Th17 cell differentiation. Recent studies reported reoxygenation of T cells in tissue culture chambers greatly enhances HIF-1a induction. Importantly, gut (hypoxic)-derived T cells entering the lung (normoxic) may face similar O2 changes. We hypothesize and will test whether the gut microbiota in combination with lung reoxygenation up- regulate HIF-1α expression in gut-derived lung CD4+ T cells, promoting their glycolytic activity and Th17 cell commitment, and worsening lung disease. Using the KikGR-photoconvertible model to trace T cells from gut to lung, our new data favor our hypothesis by showing a higher HIF-1α level in KikR (gut-derived) than KikG CD4+ T cells in lung but not spleen of SFB+ mice. CCR6 is highly expressed by Th17 cells. Our new data show that type 2 alveolar epithelial cells (AEC2) produce abundant CCL20, the CCR6 ligand in the pre-autoimmune disease phase. We will test whether lung microbiota and innate signaling are required for AEC2s’ CCL20 expression and Th17 cell recruitment by using AEC2-specific MyD88 and CCL20 depletions. Recently, gut microbiota have been shown to locally induce an intriguing gut T cell type co-expressing Rorγt+ and Foxp3+, master regulators of Th17 cells and Tregs. However, whether and how gut microbiota can remotely regulate T cell plasticity in the lung remains unknown. Our new data show that a unique population of IL-17+Foxp3+ cells is significantly increased in lung of SFB+ over SFB− mice. We will examine T cell plasticity by Treg fate mapping, and use single cell TCR analysis to analyze whether a microbiota-skewed dual TCR repertoire allows Foxp3+ T cells to acquire a Th17-like phenotype. Finally, we will use the Cre-loxP system to address the “good or evil” function of IL-17+Foxp3+ T cells in lung autoimmunity. By taking a unique approach of tracking gut-lung crosstalk, this proposal permits studies to reveal the etiology of gut-lung axis, helping to pave the way for the designing of future therapies to combat gut-lung axis-related diseases.

项目摘要。肺部并发症是类风湿性关节炎（RA）患者常见且主要的死亡原因。治疗方法有限，关节炎调节药物实际上会使 RA 患者的肺部疾病恶化，但效果甚微众所周知，与 RA 相关的肺部发病机制是肠道和肠道微生物群具有很强的影响力。从机制上讲，这种被称为肠肺轴的现象的影响很差。我们报道了通过肠-肺通讯，肠道共生的分段丝状细菌。 (SFB) 能够扩增表达双 T 细胞受体 (TCR) 的 T 辅助 17 (Th17) 细胞，从而导致肺三级淋巴结构（TLS）的病变通常与自身免疫患者的不良预后相关。肠肺轴，我们建议解决 SFB 用于促进 Th17 细胞的机制反应、肠肺迁移和肺缺氧诱导因子 1α (HIF-1α) 感知 O2。缺氧组织，例如肠道和发炎组织，已知可增强糖酵解并促进 Th17 细胞最近的研究报告称，组织培养室中 T 细胞的再氧化作用大大增强。重要的是，肠道（缺氧）来源的 T 细胞进入肺部（常氧）可能面临类似的 O2。我们已经着手并将测试肠道微生物群是否与肺部再氧合作用相结合。调节肠源性肺 CD4+ T 细胞中 HIF-1α 的表达，促进其糖酵解活性和 Th17 细胞使用 KikGR 光转换模型追踪 T 细胞从肠道到肺部疾病的恶化。肺，我们的新数据显示 KikR（肠道来源）中的 HIF-1α 水平高于 KikG CD4+，从而支持了我们的假设我们的新数据表明，SFB+ 小鼠的肺中 T 细胞高表达，但脾脏中则不然。 2 型肺泡上皮细胞 (AEC2) 产生丰富的 CCL20，即自身免疫前期的 CCR6 配体我们将测试 AEC2 的 CCL20 是否需要肺部微生物群和先天信号传导。最近，通过使用 AEC2 特异性 MyD88 和 CCL20 耗竭来进行表达和 Th17 细胞招募。微生物群已被证明可以局部诱导一种有趣的肠道 T 细胞类型，共表达 Rorγt+ 和 Foxp3+，然而，肠道微生物群是否以及如何远程调节 T 细胞。肺中的细胞可塑性仍然未知。我们的新数据表明，IL-17+Foxp3+ 细胞的独特群体。与 SFB− 小鼠相比，SFB+ 小鼠的肺中 T 细胞可塑性显着增加。作图，并使用单细胞 TCR 分析来分析微生物群倾斜的双重 TCR 库是否允许 Foxp3+ T 细胞获得类似 Th17 的表型最后，我们将使用 Cre-loxP 系统来解决“好”问题。通过采取独特的追踪肠肺的方法，研究IL-17+Foxp3+ T细胞在肺自身免疫中的“或邪恶”功能。串扰，该提案允许研究揭示肠肺轴的病因学，有助于为设计未来的疗法来对抗肠肺轴相关疾病。