Neuropeptide-mediated regulation of antihelminth immunity

神经肽介导的抗蠕虫免疫调节

• 批准号: 10120198
• 负责人: David Artis
• 金额: $ 65.83万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10120198
• 关键词: Address; Basophils; Binding; Body Temperature; Bombesin; Bombesin Receptor; Cell Culture System; Cells; Characteristics; Child; Chronic; Complex; Data; Development; Eosinophilia; Equilibrium; Event; Exhibits; Family; Family member; Gastrointestinal tract structure; Generations; Genetic Transcription; Glucose; Growth; Helminths; Helper-Inducer T-Lymphocyte; Hematopoietic; Hookworms; Human; Immune; Immune response; Immune system; Immunity; Immunologic Receptors; In Vitro; Individual; Infection; Infection prevention; Inflammation; Inflammatory Response; Knowledge; Ligands; LoxP-flanked allele; Lung; Lymphocyte; Lymphoid Cell; Malnutrition; Mediating; Mucous body substance; Mus; Muscle Contraction; Nervous system structure; Neuraxis; Neuromedin U; Neurons; Neuropeptide Receptor; Neuropeptides; Nippostrongylus; Outcome; Parasites; Pathology; Pathway interactions; Patients; Pattern; Peptides; Population; Prevalence; Production; Public Health; Publishing; Pulmonary Pathology; Receptor Signaling; Recombinants; Regulation; Reporting; Respiratory physiology; Risk; Role; Signal Pathway; Signal Transduction; Smooth Muscle; Testing; Therapeutic Uses; Tissues; base; cell growth; cell type; cholinergic neuron; combat; cytokine; health economics; helminth infection; immunopathology; in vivo; inhibitor/antagonist; insight; mouse model; neuromedin B; novel; novel therapeutic intervention; prevent; receptor; receptor expression; response

PROJECT SUMMARY Helminth parasites, including hookworms, infect approximately 2 billion people worldwide and represent a significant public health concern. To combat these parasites, the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens, but also subsequently restricting that inflammation once the infectious threat is eliminated. When properly regulated, this allows for protective immunity to be achieved without the development of unwanted immunopathology. It is well established that type 2 inflammation, characteristic of helminth-induced immune responses in humans and mice, is initiated via the production of type 2 cytokines by group 2 innate lymphoid cells (ILC2s) and type 2 T helper (TH2) cells. The activation of both innate and adaptive lymphocytes results in the induction of smooth muscle contraction, eosinophilia, mucus production and the population expansion of basophils. Despite our knowledge of the factors that promote type 2 inflammation, the mechanisms that restrict its ability to promote immunopathology remain poorly defined. Our preliminary studies revealed that helminth-induced ILC2 responses, type 2 cytokine production, lung eosinophilia and mucus production are significantly elevated following the depletion of basophils. Moreover, depletion of basophils resulted in dramatic lung pathology and decreased lung function. Strikingly, our new studies also revealed that ILC2s activated in the absence of basophils failed to upregulate expression of the receptor for the neuropeptide neuromedin b (Nmb). Further, delivery of Nmb to helminth-infected mice resulted in reduced ILC2 responses, eosinophilia and mucus production. These data suggest that Nmb is a potent inhibitor of type 2 inflammation. Nmb belongs to the bombesin-like family of neuropeptides consisting of neuromedin B, N, S and U. Importantly, neuromedin U was recently shown to be an important positive regulator of helminth- induced ILC2 responses. Collectively, our studies suggesting that Nmu and Nmb operate as neuropeptide ‘rheostat’ that properly balances helminth-induced inflammation. Based on our strong preliminary studies and generation of novel Nmbr-floxed and Nmur-Cre mouse models, three specific aims will address the following questions: (i) Do helminth-induced basophils regulate Neuromedin b receptor expression on immune cells, (ii) Does Nmb restrict the activation of multiple immune cells in a manner that properly regulates helminth-induced inflammation, and (iii) Do Nmu and Nmb directly counterbalance each other and operate as a neuropeptide rheostat? Collectively, these studies will interrogate novel mechanisms through which type 2 cytokine- mediated immunity and inflammation are negatively regulated. Defining the mechanisms through which basophils initiate a Nmu/Nmb-mediated rheostat may inform new therapeutic strategies to treat helminth- induced immunopathology.

项目摘要 蠕虫寄生虫，包括钩虫，感染了全世界大约20亿人， 重大公共卫生问题。为了对抗这些寄生虫，哺乳动物的免疫系统已经进化 机制，以保持微妙的平衡，促进有益的炎症需要减少 寄生虫负担，而且一旦传染性威胁被消除，也随后限制炎症。 当适当调节时，这允许实现保护性免疫，而不会产生 不必要的免疫病理学。已经确定，2型炎症，蠕虫引起的特征， 人和小鼠的免疫应答，是通过2型细胞因子的产生启动的， 淋巴样细胞（ILC 2）和2型T辅助细胞（TH 2）。先天性和适应性淋巴细胞的激活 导致诱导平滑肌收缩、嗜酸性粒细胞增多、粘液产生， 嗜碱性粒细胞增多。尽管我们知道促进2型炎症的因素， 限制其促进免疫病理学的能力的机制仍然不清楚。我们的初步 研究表明，蠕虫诱导的ILC 2反应、2型细胞因子产生、肺嗜酸性粒细胞增多和 在嗜碱性粒细胞耗尽后粘液产生显著升高。此外， 嗜碱性粒细胞导致显著的肺病理学和肺功能降低。引人注目的是，我们的新研究还 结果显示，在嗜碱性粒细胞缺乏的情况下激活的ILC 2不能上调ILC 2受体的表达。 神经肽神经介肽B（Nmb）。此外，将Nmb递送到蠕虫感染的小鼠导致减少的细胞毒性。 ILC 2反应、嗜酸性粒细胞增多和粘液产生。这些数据表明，Nmb是一种有效的抑制剂， 2炎症Nmb属于蛙皮素样神经肽家族，由神经介肽B、N、S 和联合重要的是，神经介肽U最近被证明是蠕虫的重要正调节因子- 诱导ILC 2应答。总的来说，我们的研究表明，Nmu和Nmb作为神经肽 “变阻器”，适当平衡蠕虫引起的炎症。基于我们强大的初步研究， 为了产生新的Nmbr-floxed和Nmur-Cre小鼠模型，三个具体目标将解决以下问题 问题：（i）蠕虫诱导的嗜碱性粒细胞是否调节免疫细胞上神经介肽B受体的表达，（ii） Nmb是否以适当调节蠕虫诱导的免疫细胞的方式限制多种免疫细胞的激活？ 炎症，和（iii）Nmu和Nmb是否直接相互平衡并作为神经肽起作用 变阻器？总的来说，这些研究将探讨新的机制，通过2型细胞因子- 介导的免疫和炎症受到负调节。确定机制， 嗜碱性粒细胞启动Nmu/Nmb-mediated变阻器可能为治疗蠕虫的新治疗策略提供信息- 诱导免疫病理学