The role of chemoattractant receptors in central nervous system diseases

趋化受体在中枢神经系统疾病中的作用

• 批准号: 8274293
• 负责人: PABLO IRIBARREN
• 金额: $ 4.97万
• 依托单位: NATIONAL RESEARCH COUNCIL OF ARGENTINA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274293
• 关键词: AIDS Dementia Complex; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Blood Vessels; Brain; CX3CL1 gene; Cell Death Induction; Cell Line; Central Nervous System Diseases; Central Nervous System Infections; Chemotaxis; Data; Deposition; Equilibrium; Filament; Fractalkine; Gliosis; Goals; Health; Homologous Gene; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Lesion; Ligands; Mediating; Microglia; Molecular Target; Mus; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oxygen; Pathogenesis; Patients; Peptides; Peripheral; Play; Process; Receptor Down-Regulation; Regulation; Regulatory Pathway; Role; Senile Plaques; Signal Pathway; Signal Transduction; Site; Stimulus; Synapses; TNF gene; Up-Regulation; chemokine; cytokine; fMet-Leu-Phe receptor; insight; leukocyte activation; macrophage; mannose receptor; monocyte; neuroinflammation; neurotoxicity; receptor function; receptor mediated endocytosis; response; tau Proteins; tau mutation; therapeutic development

DESCRIPTION (provided by applicant): Inflammation plays an important role in central nervous system (CNS) infection and the progression of neurodegenerative diseases such as HIV-associated dementia and Alzheimer's disease (AD). The presence of an abundant number of activated microglial cells in amyloid plaques and the elevated levels of pro-inflammatory molecules in CNS support the contribution of chemoattractant receptors and inflammation to the pathogenesis of AD. It is clear that a balance between pro- and anti-inflammatory signals in the CNS is important in the initiation and progression of AD. Interleukin 4 (IL-4) and other anti-inflammatory cytokines, such as IL-13, differentially regulate microglial responses to amyloid beta 1-42 (A242), the pathogenic peptide in AD; which indicates that IL-4 and IL-13 have the potential to regulate inflammatory processes associated with this neurodegenerative disease. All these evidences prompted us to hypothesize that IL-4, by regulating the activation of microglial cells and its expression of key chemoattractant receptors that participate in neuroinflammation, may provide protection against the deleterious effects of proinflammatory stimuli in the CNS. The specific aims of this study are: 1) To evaluate the effects of IL-4 on the survival and activation of microglial cells. 2) To examine the regulation of chemoattractant receptors in macrophages and microglia by interleukin 4. 3) To further dissect the signaling pathways involved in the effects of IL-4 on microglial cells. Significance: The completion of these goals will provide insights into the role of IL-4 in the regulation of neuroinflammation and the definition of potential molecular targets for the development of therapeutic approaches to treat AD and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The presence of an abundant number of activated microglial cells in the brain support the contribution of chemoattractant receptors and inflammation to the pathogenesis of Alzheimer's disease (AD). Interleukin 4 (IL- 4) may provide protection against the deleterious effects of pro-inflammatory stimuli in the central nervous system. The completion of the goals proposed in this project will provide insights into the role of IL-4 in the regulation of neuroinflammation and the definition of potential molecular targets for the development of therapeutic approaches to treat AD and other neurodegenerative diseases.

描述(申请人提供)：炎症在中枢神经系统(CNS)感染和神经退行性疾病(如HIV相关性痴呆症和阿尔茨海默病(AD))的进展中起着重要作用。淀粉样斑块中大量活化的小胶质细胞的存在和中枢神经系统促炎分子水平的升高支持了趋化受体和炎症在AD发病中的作用。很明显，中枢神经系统中促炎和抗炎信号之间的平衡在AD的发生和发展中是重要的。白介素4(IL-4)和其他抗炎细胞因子，如IL-13，对小胶质细胞对淀粉样蛋白β1-42(A242)的反应有不同的调节作用，这表明IL-4和IL-13有可能调节与这种神经退行性疾病相关的炎症过程。所有这些证据促使我们推测，IL-4通过调节小胶质细胞的激活及其参与神经炎症的关键趋化受体的表达，可能对中枢神经系统的促炎刺激的有害影响起到保护作用。本研究的具体目的是：1)探讨IL-4对小胶质细胞存活和活化的影响。2)研究IL-4对巨噬细胞和小胶质细胞趋化受体的调节作用。3)进一步剖析IL-4影响小胶质细胞的信号转导途径。意义：这些目标的完成将提供对IL-4在调节神经炎症中的作用的洞察，并为开发治疗AD和神经退行性疾病的治疗方法定义潜在的分子靶点。公共卫生相关性：大脑中大量激活的小胶质细胞的存在支持化学吸引物受体和炎症在阿尔茨海默病(AD)发病机制中的作用。白介素4(IL-4)可能对中枢神经系统促炎刺激的有害影响起到保护作用。本项目提出的目标的完成将提供对IL-4在调节神经炎症中的作用的洞察，并为开发治疗AD和其他神经退行性疾病的治疗方法定义潜在的分子靶点。

项目成果

Toll-like receptors are key players in neurodegeneration.

• DOI: 10.1016/j.intimp.2011.05.006
• 发表时间: 2011-10
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Arroyo DS;Soria JA;Gaviglio EA;Rodriguez-Galan MC;Iribarren P
• 通讯作者: Iribarren P

Systemic sterile induced-co-expression of IL-12 and IL-18 drive IFN-γ-dependent activation of microglia and recruitment of MHC-II-expressing inflammatory monocytes into the brain.

IL-12和IL-18驱动IFN-γ依赖性小胶质细胞的IL-12和IL-18驱动型诱导的无菌表达，并募集MHC-II表达炎症单核细胞到大脑中。

• DOI: 10.1016/j.intimp.2022.108546
• 发表时间: 2022-04
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Gaviglio EA;Peralta Ramos JM;Arroyo DS;Bussi C;Iribarren P;Rodriguez-Galan MC
• 通讯作者: Rodriguez-Galan MC

Autophagy down regulates pro-inflammatory mediators in BV2 microglial cells and rescues both LPS and alpha-synuclein induced neuronal cell death.

• DOI: 10.1038/srep43153
• 发表时间: 2017-03-03
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bussi C;Peralta Ramos JM;Arroyo DS;Gaviglio EA;Gallea JI;Wang JM;Celej MS;Iribarren P
• 通讯作者: Iribarren P

Autophagy in inflammation, infection, neurodegeneration and cancer.

• DOI: 10.1016/j.intimp.2013.11.001
• 发表时间: 2014-01
• 期刊: International immunopharmacology
• 影响因子: 5.6
• 作者: Arroyo DS;Gaviglio EA;Peralta Ramos JM;Bussi C;Rodriguez-Galan MC;Iribarren P
• 通讯作者: Iribarren P

Interleukin 4 induces the apoptosis of mouse microglial cells by a caspase-dependent mechanism.

• DOI: 10.1016/j.nbd.2011.05.010
• 发表时间: 2011-09
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Soria, Javier A.;Arroyo, Daniela S.;Gaviglio, Emilia A.;Rodriguez-Galan, Maria C.;Wang, Ji Ming;Iribarren, Pablo
• 通讯作者: Iribarren, Pablo