Neuropeptide-mediated regulation of antihelminth immunity

神经肽介导的抗蠕虫免疫调节

• 批准号: 10468776
• 负责人: David Artis
• 金额: $ 64.97万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 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/10468776
• 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; Persons; 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; 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.

项目总结 包括钩虫在内的蠕虫寄生虫感染着全球约20亿人，代表着一种 严重的公共卫生问题。为了对抗这些寄生虫，哺乳动物的免疫系统进化了 在促进有益炎症之间保持微妙平衡的机制需要减少 寄生虫的负担，但随后也限制这种炎症一旦感染威胁被消除。 如果受到适当的监管，这就可以实现保护性免疫，而不会出现 不受欢迎的免疫病理学。众所周知，以蠕虫为特征的II型炎症 人类和小鼠的免疫反应是通过第二组先天产生的2型细胞因子来启动的 淋巴样细胞(ILC2)和2型辅助性T细胞(TH2)。先天和获得性淋巴细胞的激活 结果在诱发平滑肌收缩、嗜酸性粒细胞增多、粘液产生和人口 嗜碱性粒细胞的扩张。尽管我们知道促进II型炎症的因素，但 限制其促进免疫病理学能力的机制仍未明确。我们的预赛 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，粘液产量显著增加。此外，耗尽了 嗜碱性粒细胞导致严重的肺部病变和肺功能下降。令人惊讶的是，我们的新研究也 发现在没有嗜碱性粒细胞的情况下被激活的ILC2不能上调受体的表达 神经肽NMB(NMB)。此外，给受蠕虫感染的小鼠注射NMB可减少 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 2炎症。NMB属于蛙素样神经肽家族，由神经梅毒素B、N、S组成 重要的是，神经梅毒素U最近被证明是蠕虫的一个重要的正向调节因子。 诱导ILC2反应。总而言之，我们的研究表明NMU和NMB作为神经肽发挥作用 “变色器”能适当地平衡蠕虫引起的炎症。基于我们强大的初步研究和 新一代NMbR-FLOXED和NMUR-CRE小鼠模型的三个具体目标将解决以下问题 问题：(I)蠕虫诱导的嗜碱性细胞是否调节免疫细胞上神经介素b受体的表达，(Ii) NMB是否以适当调节蠕虫诱导的方式来限制多个免疫细胞的激活 炎症，以及(Iii)NMU和NMB是否直接相互抵消并作为神经肽发挥作用 变阻器？总的来说，这些研究将询问新的机制，通过这些机制，2型细胞因子- 介导的免疫和炎症是负调控的。定义机制，通过这些机制 嗜碱性粒细胞启动NMU/NMB介导的变阻器可能提供治疗蠕虫的新治疗策略- 诱导免疫病理学。