Neuropeptide-mediated regulation of antihelminth immunity

神经肽介导的抗蠕虫免疫调节

• 批准号: 10265558
• 负责人: David Artis
• 金额: $ 64.72万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265558
• 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; 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; pulmonary function; 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.

项目概要 包括钩虫在内的蠕虫寄生虫感染了全世界约 20 亿人，代表了 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 促进有益炎症和减少炎症之间维持微妙平衡的机制 寄生虫负担，而且一旦感染威胁消除，炎症也会随之受到限制。 当适当调节时，这可以实现保护性免疫力，而无需发展 不需要的免疫病理学。众所周知，2 型炎症（蠕虫引起的特征） 人类和小鼠的免疫反应是通过第 2 组先天性细胞因子的产生来启动的 淋巴细胞 (ILC2) 和 2 型 T 辅助细胞 (TH2)。先天性淋巴细胞和适应性淋巴细胞的激活 导致平滑肌收缩、嗜酸性粒细胞增多、粘液产生和群体的诱导 嗜碱性粒细胞扩张。尽管我们了解促进 2 型炎症的因素， 限制其促进免疫病理学能力的机制仍然不明确。我们的初步 研究表明，蠕虫诱导的 ILC2 反应、2 型细胞因子的产生、肺嗜酸性粒细胞增多和 嗜碱性粒细胞耗尽后，粘液产量显着增加。此外，耗尽 嗜碱性粒细胞导致严重的肺部病变和肺功能下降。引人注目的是，我们的新研究还 研究表明，在没有嗜碱性粒细胞的情况下激活的 ILC2 未能上调受体的表达 神经肽神经调节素 b (Nmb)。此外，将 Nmb 递送给感染蠕虫的小鼠会导致 ILC2 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 属于铃蟾肽样神经肽家族，由神经调节肽 B、N、S 组成 重要的是，神经调节素 U 最近被证明是蠕虫的重要正调节剂 诱导ILC2反应。总的来说，我们的研究表明 Nmu 和 Nmb 作为神经肽起作用 “变阻器”可以适当平衡蠕虫引起的炎症。基于我们强有力的初步研究和 生成新型 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的 Neuromedin b 受体表达，(ii) Nmb 是否以适当调节蠕虫诱导的方式限制多种免疫细胞的激活 (iii) Nmu 和 Nmb 是否直接相互平衡并作为神经肽发挥作用 变阻器？总的来说，这些研究将探讨 2 型细胞因子的新机制。 介导的免疫和炎症受到负向调节。定义机制 嗜碱性粒细胞启动 Nmu/Nmb 介导的变阻器可能会为治疗蠕虫提供新的治疗策略 诱导免疫病理学。