Endocytic Regulation of Inflammation

炎症的内吞调节

基本信息

批准号：
9312915
负责人：
LINDA H SHAPIRO
金额：
$ 4.76万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312915
关键词：
Address Animals Antiviral Response Autoimmunity Binding Cell Adhesion Molecules Cell physiology Cell surface Cells Clinical Complex Data Defect Dendritic Cells Development Disease Dissection Endocytosis Endothelial Cells Equilibrium Figs - dietary Goals Healed Health Hematopoietic ITGAX gene Immune response Immune system Impaired wound healing In Vitro Individual Inflammation Inflammatory Injury Interferon Type I Interferon-beta Interferons Interleukin-10 Ischemia Knowledge Ligands Ligation Marrow Mediating Mission Modeling Molecular Mus Muscle Myelogenous Myeloid Cells Natural Immunity Necrosis Nitrates Obesity Organelles Outcome Pathogenesis Pathology Pathway interactions Pattern Peptide Hydrolases Perfusion Peripheral arterial disease Process Production Recovery Regulation Research Role Sentinel Signal Pathway Signal Transduction Signal Transduction Pathway Site Stem cells TLR4 gene Therapeutic Tissues Toll-like receptors Transplantation United States National Institutes of Health Wound Healing alanine aminopeptidase angiogenesis arm base cell type cytokine design femoral artery genetic regulatory protein healing improved in vivo Model interest macrophage neutrophil new therapeutic target novel pathogen prevent receptor receptor mediated endocytosis receptor recycling response response to injury therapeutic target tissue repair

项目摘要

DESCRIPTION (provided by applicant): CD13 is a large, multifunctional cell surface peptidase that is constitutively expressed on all lineages of myeloid cells (among others) and upregulated on endothelial cells at sites of angiogenesis and inflammation. Collectively, our recent studies demonstrate that CD13 regulates endocytosis of receptors of disparate classes in different cell types to control downstream signal transduction pathways, implicating a role for CD13 in fundamental cellular processes. More recently, we showed that in dendritic cells (DCs) CD13 regulates endocytosis of the toll-like receptor TLR4 which is a critical sentinel of the innate immune response to pathogens via PAMPs (pathogen-associated molecular patterns) and DAMPs (danger associated molecular patterns). Binding of DAMPs to macrophage and DC TLR4 in the absence of CD13 leads to an unbalanced cytokine response and aberrantly high levels of type I interferons (IFNs) due to skewed endocytic-signaling pathways. Although beneficial in anti-viral responses, strong IFN responses clearly exacerbate the patho- genesis of TLR4-binding PAMPs and DAMPs. Furthermore, we have additional evidence implicating CD13 in receptor recycling to the cell surface. To model this in vivo we subjected wild type and CD13null animals to permanent femoral artery dissection, which releases endogenous ligands that TLR4 recognizes as DAMPs. Functionally, CD13null mice have strikingly impaired ambulation and perfusion recovery and more necrosis consistent with impaired healing. Furthermore, cytokine profiles in the ischemic muscle showed markedly increased levels of IFN-ß and IL-10 consistent with our in vitro data and with studies where TLR4 engagement by PAMPs or DAMPs leads to exaggerated pathology suggesting that CD13 regulates the balance between pro-inflammatory and IFN-generating signal transduction in myeloid cells. Furthermore, marrow transplant studies demonstrating that CD13null donor hematopoietic cells are unable to rescue perfusion and function in wild type ischemic muscles validate this notion and highlights the importance of fully understanding the mechanistic basis of this novel regulator. Finally, while it is clear that the individual subsets of myeloid cells of the innate immune response orchestrate subsequent steps in the healing process, their relative contributions and specific roles are largely unknown. Pertinent to this proposal, macrophage and DC TLR4 signaling occurs via both cell surface and endocytic mechanisms supporting discrete regulatory processes and cell-specific roles for these largely uncharacterized pathways in distinct cell types. Therefore, through its regulation of endocytosis, we propose that myeloid CD13 is a functional regulator of innate immunity and dissection of the relative contributions of CD13 expressed on pan-myeloid (lysM-cre) and DCs (CD11c-cre) to these regulatory processes will clearly increase our understanding of myeloid cells in response to ischemia, information essential to the design of strategies to regulate healing by manipulating this novel target.

描述（由适用提供）：CD13是一种大型的多功能细胞表面胡椒酶，在髓样细胞的所有谱系（以及其他）上始终表达，并在血管生成和炎症部位对内皮细胞进行了更新。总体而言，我们最近的研究表明，CD13调节不同细胞类型中不同类别的受体的内吞作用以控制下游信号转导途径，这暗示了CD13在基本细胞过程中的作用。最近，我们表明，在树突状细胞（DCS）中，CD13调节了类似类似受体的受体TLR4的内吞作用，这是通过PAMP（病原体相关的分子模式）和damps（危险相关的分子模式）对病原体的先天免疫增强响应的关键前哨。在不存在CD13的情况下，潮湿与巨噬细胞和DC TLR4的结合导致细胞因子反应不平衡，并且由于倾斜的内吞signal途径而导致的I型干扰素（IFN）异常高。尽管对抗病毒反应有益，但强烈的IFN反应显然加剧了TLR4结合弹跳和潮湿的病情。此外，在受体回收到细胞表面的受体回收中，我们还有其他证据隐式CD13。为了模拟这种体内，我们将野生型和CD13NULL动物进行了永久性股动脉夹层，该动脉释放了TLR4识别为潮湿的内源性配体。从功能上讲，CD13NULL小鼠的救护车和灌注恢复严重受损，并且与愈合受损一致。此外，缺血性肌肉中的细胞因子谱图显着增加IFN-β和IL-10水平，与我们的体外数据一致，并且与研究的研究相一致，在该研究中，PAMP或潮湿的TLR4参与性会导致夸张的病理学表明CD13调节了促炎和IFN造成的IFN启发性信号和IFN信号传递之间的平衡。此外，骨髓移植研究表明，CD13NULL供体造血细胞无法挽救灌注和功能，在野生型缺血性肌肉中验证了这一概念，并突出了完全了解该新调节剂的机械基础的重要性。最后，而显然，先天免疫响应的髓样细胞的各个子集在康复过程中编排了随后的步骤，它们的相对贡献和特定作用在很大程度上是未知的。与该建议相关，巨噬细胞和DC TLR4信号通过支持离散调节过程和细胞特异性作用的细胞表面和内吞机制发生，用于这些不同的细胞类型中这些途径。因此，通过调节内吞作用，我们提出，髓样CD13是先天免疫的功能调节因子和对泛乳突（lysm-cre）和DCS（lysm-cre）和DCS（CD11C-CRE）对这些调节过程的相对贡献的相对贡献的解剖和解剖，这清楚地提高了我们对我们对肌动型细胞的策略的理解，从而使我们对issemii的疗法的理解更加重要。新目标。