Perinatal Dysbiosis, Lung Development and Asthma

围产期生态失调、肺部发育和哮喘

基本信息

批准号：
10625311
负责人：
Ian Paul Lewkowich
金额：
$ 39.86万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2020-06-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10625311
关键词：
Acetates Adolescent Adult Allergens Alveolar Animal Model Animals Antibiotics Asthma Automobile Driving Biological Assay Birth Breast Feeding Cell secretion Cells Cesarean section Communities Cues Data Development Disease Elderly Endothelium Environmental Exposure Epithelial Cells Epithelium Equilibrium Exposure to Extrinsic asthma Genetic Predisposition to Disease Goals Health Status Homeostasis Human IL17 gene Immune Immune response Intervention Life Link Lung Lung immune response Mediating Mesenchymal Mesenchyme Mucosal Immune System Mucous Membrane Mus Nature Neonatal Organoids Pathogenesis Pathogenicity Pattern Perinatal Perinatal Exposure Permeability Phenocopy Phenotype Play Predisposition Prevalence Production Public Health Pyroglyphidae Regulation Risk Risk Factors Role Severities Signal Pathway Signal Transduction Site Structural defect Supplementation Surface T-Lymphocyte Testing Therapeutic Work airway hyperresponsiveness chemokine chronic inflammatory disease cigarette smoke commensal bacteria design dysbiosis early life exposure epidemiologic data human disease in vivo insight interleukin-22 knockout animal lung development lung health microbial microbial colonization microbiome novel offspring perinatal period prophylactic receptor recruit response risk mitigation

项目摘要

Environmental exposures that alter asthma risk (C-section, breast feeding) also influence microbial colonization. Dysbiosis regulates mucosal IL-17A and IL-22 levels differently, reducing IL-22 production while enhancing the recruitment of IL-17A-producing cells. As IL-22 mediates homeostasis at mucosal surfaces, and IL-17A production is associated more severe asthma phenotypes, this suggests dysbiosis-induced regulation of asthma pathogenesis may involve an underappreciated dysregulation of the IL-22/IL-17A balance. Our preliminary data show that: (1) perinatal dysbiosis induces lung structural changes, increased baseline airway hyperreactivity (AHR), and exaggerated house dust mite (HDM)-induced asthma phenotype (more severe AHR, elevated chemokine production, enhanced recruitment of IL-17A-producing cells); (2) organoids derived from dysbiosis- exposed epithelial cells demonstrate reduced colony forming efficiency and increased HDM-stimulated chemokine production; (3) IL-17A blockade abrogates perinatal dysbiosis-augmented, HDM-induced AHR; (4) perinatal IL-22 blockade recapitulates some features of perinatal dysbiosis (increased airway responses and lung permeability in HDM-naïve adolescent mice); (5) IL-22Ra1 expression is regulated developmentally on pulmonary mesenchymal cells; and (6) supplementation with acetate reverses perinatal dysbiosis-induced alveolar permeability. Thus, we hypothesize that perinatal dysbiosis-induced reduction in neonatal mesenchymal IL-22 signaling drives altered lung development, increased allergen-driven recruitment of IL-17A-producing cells and more severe asthma later in life, and that bacterial metabolite supplementation will reverse these phenotypes. This hypothesis will be tested in three Aims: Aim 1: To define mechanisms driving increased allergen-induced IL-17A-producing cell recruitment and identify the IL-17A-secreting cells driving severe asthma after perinatal dysbiosis, we will determine if perinatal dysbiosis influences immune cell responsiveness to chemotactic signaling, identify pulmonary structural cells responsible for increased chemokine production, and identify which IL-17A-producing ILCs are necessary and sufficient to drive the structural and asthma phenotypes observed after perinatal dysbiosis. Aim 2: To determine if perinatal IL-22 signaling in mesenchymal cells influences pulmonary development, baseline AHR, and the severity of allergen- driven AHR, we will target IL-22-activated signaling pathways in mesenchymal cells during critical neonatal windows in control mice, and supplement animals exposed to perinatal dysbiosis with rIL-22 or IL-22 producing cells, and assess the impact on dysbiosis-induced phenotypes, Aim 3: To determine if dysbiosis-induced alterations in lung development or asthma severity can be reversed by supplementation with bacterial metabolites, we will test the capacity of bacterial metabolites administered prophylactically and therapeutically to reverse dysbiosis-induced phenotypes. Collectively, these studies will elucidate the mechanisms by which perinatal dysbiosis influences asthma development.

环境暴露改变哮喘风险（剖腹产，母乳喂养）也会影响微生物定植。营养不良调节粘膜IL-17A和IL-22水平有所不同，从而降低IL-22的产生，同时增强募集IL-17A产生细胞。随着IL-22介导粘膜表面的体内稳态，IL-17A 生产是更严重的哮喘表型，这表明营养不良引起的哮喘调节发病机理可能涉及IL-22/IL-17A平衡的失调不足。我们的初步数据证明：（1）围产期营养不良诱导肺结构变化，基线气道高反应性增加（AHR），夸张的房屋尘螨（HDM）诱导的哮喘表型（更严重的AHR，升高趋化因子产生，增强IL-17A产生细胞的募集）；（2）源自营养不良的类器官 - 裸露的上皮细胞表现出降低的菌落形成效率，并提高了HDM刺激趋化因子产生；（3）IL-17A阻断消除了围产期营养不良的增强，HDM诱导的AHR；（4）围产期IL-22 blocade概括了围产期营养不良的某些特征（气道反应增加和 HDM不含青少年小鼠的肺渗透性）；（5）IL-22RA1表达在发育中受到调节肺间质细胞；（6）补充乙酸盐逆转会围产期营养不良引起的肺泡渗透性。这是我们假设围产期营养不良诱导的新生儿间充质的减少 IL-22信号传导改变了肺发育，增加了产生IL-17A的细胞的过敏素驱动的募集生命之后更严重的哮喘，而细菌补充剂会逆转这些表型。该假设将以三个目的进行检验：目标1：定义驱动机制增加过敏原诱导的IL-17A产生细胞募集并鉴定驱动严重的IL-17A分泌细胞围产期营养不良后的哮喘，我们将确定围产期营养不良是否影响免疫细胞对趋化信号传导的反应，鉴定导致趋化因子增加的肺结构细胞生产，并确定哪些IL-17A产生的ILC是必需的，足以驱动结构和围产期营养不良后观察到哮喘表型。目标2：确定围产期IL-22是否在间充质细胞影响肺发育，基线AHR和过敏原的严重程度驱动的AHR，我们将靶向临界新生儿期间间充质细胞中IL-22激活的信号通路对照小鼠的窗户，并用RIL-22或IL-22产生围产期营养不良的动物补充动物细胞，并评估对营养不良诱导的表型的影响，目的3：确定失调诱导的通过补充细菌可以逆转肺发育或哮喘严重程度的改变代谢物，我们将通过预防和治疗的细菌代谢物测试能力逆转营养不良诱导的表型。总的来说，这些研究将阐明围产期营养不良会影响哮喘发育。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prenatal antibiotics exposure does not influence experimental allergic asthma in mice.

DOI：
10.3389/fimmu.2022.937577
发表时间：
2022
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Lingel, Imke;Wilburn, Adrienne N.;Hargis, Julie;McAlees, Jaclyn W.;Laumonnier, Yves;Chougnet, Claire A.;Deshmukh, Hitesh;Koenig, Peter;Lewkowich, Ian P.;Schmudde, Inken
通讯作者：
Schmudde, Inken

Modulation of IL-4/IL-13 cytokine signaling in the context of allergic disease.