Role of the neurogenic inflammatory pathway in the genital tract immune response

神经源性炎症途径在生殖道免疫反应中的作用

• 批准号: 7860425
• 负责人: Roger G Rank
• 金额: $ 20.21万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860425
• 关键词: Acute; Address; Affect; Afferent Neurons; Antibodies; Antibody Formation; Area; Attention; B-Lymphocytes; Bacteria; Bacterial Infections; Bacteriophages; Binding; Biological Neural Networks; CXCL10 gene; CXCL9 gene; Cells; Cellular Immunity; Cervix Uteri; Chemotactic Factors; Chlamydia Infections; Chlamydia muridarum; Contact Dermatitis; Cornea; Dendritic Cells; Dendritic cell activation; Development; Disease; Endometrium; Endothelial Cells; Epithelial; Epithelial Cells; Equilibrium; Extravasation; Female; Fiber; Genital system; Heat shock proteins; Hour; IL8 gene; Immune; Immune response; Immunity; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Interferons; Interleukin-6; Lead; Lipopolysaccharides; Lymphocyte; Mammalian Oviducts; Mediating; Modeling; Mucosal Immune Responses; Mucous Membrane; Mus; NF-kappa B; Natural Killer Cells; Nerve; Nerve Fibers; Neuropeptides; Parasites; Pathogenesis; Pathologic; Pathway interactions; Peptidoglycan; Plasma; Play; Production; RANTES; Recruitment Activity; Research; Resistance; Resistance to infection; Resolution; Role; Salmonella infections; Sensory; Sexually Transmitted Diseases; Site; Study models; Substance P; Substance P Receptor; Surface; T cell response; T-Lymphocyte; Tissues; Toll-like receptors; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vasodilation; Work; cell mediated immune response; chemokine; cytokine; genital infection; macrophage; male; mast cell; monocyte; mucosal site; neutrophil; pathogen; research study; response

DESCRIPTION (provided by applicant): There are multiple mechanisms by which bacteria elicit an inflammatory response at mucosal sites; however, a pathway mediated by neuropeptides has received little attention but may be equally as important in the induction of the inflammatory response by bacteria. Neuropeptides such as substance P are released by sensory C type fiber nerves upon stimulation and bind to the neurokinin-1 receptor resulting in vasodilatation, plasma extravasation, and up-regulation of VCAM-1 and ICAM-1 on endothelial cells. Substance P may directly stimulate immune and epithelial cells via the neurokinin-1 receptor, causing the release of proinflammatory cytokines and IFN-? and activation of NF-?B. Chemotactic factors produced as a result of substance P release recruit neutrophils, monocytes, macrophages, and lymphocytes to the local site. Interestingly, the neurokinin-1 receptor is found on many essential cells of the host immune response, including T and B cells, macrophages, dendritic cells, PMNs, mast cells, and natural killer cells. Thus, substance P may be important for the induction of the innate immune response and the initiation of the adaptive response. In order to investigate a role for the neurogenic inflammatory response in bacterial infection at a mucosal site, mice will be infected in the genital tract with Chlamydia muridarum, a natural parasite of mice and a strict mucosal pathogen, infecting only the superficial epithelial layer of the genital tract, including the cervix, endometrium, and oviduct. Chlamydial infection elicits a strong acute inflammatory response which not only is responsible for the pathologic response but is also necessary to control the infection until the adaptive immune response is activated. Ultimately, a Th1 response is required for resolution of the infection and resistance to reinfection. To date there have been no studies on the role of the neurogenic inflammatory response in either the male or female genital tracts. In preliminary experiments a marked reduction in the acute inflammatory response of mice lacking substance P in the first 24 hours following chlamydial infection was observed as well as a decrease in the production of several important chemokines and cytokines, indicating that substance P may play a role in both the innate and adaptive immune responses in the genital mucosa. Thus, it is hypothesized that the neurogenic inflammatory response is essential for both the induction of the acute inflammatory response and is required for the production of a protective T cell response against bacterial infection in the genital mucosa. The focus of this proposal will be to characterize the effects of neuropeptides in the genital mucosal site on the development of the acute inflammatory response and its role in eliciting the protective cell-mediated immune response using chlamydial genital infection as a model. The Specific Aims will be 1) to determine the role of the neurogenic inflammatory response on the initiation of the innate immune response to chlamydial genital infection; 2) to determine the effect of the neuropeptides on the course and pathogenesis of chlamydial genital infection; and 3) to determine if the neurogenic inflammatory pathway affects immunity to reinfection in the genital tract. Virtually all mucosal sites have a network of neural sensory fibers which release neuropeptides upon stimulation of the nerves. It has been well known that these molecules can initiate an inflammatory response, but their role in bacterial infections at mucosal surfaces has not been addressed to a great extent. There has been no work on the role of neuropeptides in the female genital mucosa in the response to infection with sexually- transmitted bacteria. Thus, this proposal will determine the contribution of neuropeptides to genital tract immunity and disease and may lead to the description of a new paradigm in our understanding of the balance of resistance versus disease in the genital tract.

描述（由申请人提供）：有多种机制，细菌在粘膜部位引起炎症反应；但是，神经肽介导的途径很少受到关注，但在细菌诱导炎症反应中同样重要。刺激后感觉C型纤维神经释放神经肽，并与内皮细胞上VCAM-1和ICAM-1的上调。物质P可以直接通过Neurokinin-1受体刺激免疫和上皮细胞，从而导致促炎细胞因子和IFN-的释放？和nf-？b的激活。 p释放了p释放的趋化因子P释放到局部部位募集中性粒细胞，单核细胞，巨噬细胞和淋巴细胞。有趣的是，在宿主免疫反应的许多必需细胞中发现了神经蛋白-1受体，包括T和B细胞，巨噬细胞，树突状细胞，PMN，肥大细胞和天然杀伤细胞。因此，物质P对于诱导先天免疫反应和适应性反应的启动可能很重要。 In order to investigate a role for the neurogenic inflammatory response in bacterial infection at a mucosal site, mice will be infected in the genital tract with Chlamydia muridarum, a natural parasite of mice and a strict mucosal pathogen, infecting only the superficial epithelial layer of the genital tract, including the cervix, endometrium, and oviduct.衣原体感染引起了强烈的急性炎症反应，这不仅是病理反应的原因，而且还需要控制感染，直到激活适应性免疫反应为止。最终，解决感染和重新感染的抗性需要TH1反应。迄今为止，还没有关于雄性或女性生殖道中神经源性炎症反应的作用的研究。在初步实验中，观察到衣原体感染后的最初24小时缺乏物质P的小鼠的急性炎症反应显着降低，并且减少了几种重要的趋化因子和细胞因子的产生，表明物质P在植物和适应性的免疫反应中可能在纯粹的植物Mucosa中起作用。因此，假设神经源性炎症反应对于诱导急性炎症反应至关重要，并且对于在生殖器粘膜中抗细菌感染的保护性T细胞反应是必需的。该提案的重点是表征神经肽在生殖器粘膜部位对急性炎症反应发展的作用及其在引发使用衣原体生殖器感染作为模型的保护性细胞介导的免疫反应中的作用。具体目的是1）确定神经发生炎症反应在开始对衣原体生殖器感染的先天免疫反应中的作用； 2）确定神经肽对衣原体生殖器感染的病程和发病机理的影响； 3）确定神经发生炎症途径是否影响生殖道中的免疫力。几乎所有粘膜位点都有一个神经感觉纤维网络，这些神经感觉纤维在神经的刺激时释放神经肽。众所周知，这些分子可以引发炎症反应，但是它们在粘膜表面的细菌感染中的作用尚未在很大程度上得到解决。神经肽在女性生殖器粘膜中的作用在对性传播细菌感染中的反应中尚无作用。因此，该建议将确定神经肽对生殖道免疫和疾病的贡献，并可能导致对新范式的描述，以理解我们对生殖道中抗药性与疾病的平衡的理解。