Endocytic Regulation of Inflammation

炎症的内吞调节

• 批准号: 9509485
• 负责人: LINDA H SHAPIRO
• 金额: $ 40.93万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9509485
• 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; Goals; Hematopoietic; ITGAX gene; Immune response; Impaired wound healing; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Injury; Innate Immune Response; Innate Immune System; 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; cell type; clinically translatable; cytokine; design; femoral artery; genetic regulatory protein; healing; improved; in vivo Model; interest; macrophage; neutrophil; new therapeutic target; novel; pathogen; prevent; public health relevance; receptor; receptor mediated endocytosis; receptor recycling; response; response to injury; therapeutic target; tissue repair

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(申请人提供)：CD13是一种大的、多功能的细胞表面多肽酶，在所有髓系细胞(包括其他细胞系)上结构性表达，在血管生成和炎症部位的内皮细胞上上调。综上所述，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，这意味着CD13在基本的细胞过程中发挥作用。最近，我们发现在树突状细胞(DC)中，CD13调节Toll样受体TLR4的内吞作用，Toll样受体TLR4是通过PAMPs(病原体相关分子模式)和DAMPS(危险相关分子模式)实现对病原体的先天性免疫反应的关键哨兵。在缺乏CD13的情况下，DAMPS与巨噬细胞和DC TLR4结合会导致细胞因子反应失衡，并由于扭曲的内吞信号通路而导致I型干扰素(IFN)水平异常高。虽然在抗病毒反应中有益，但强烈的干扰素反应明显加剧了TLR4结合的PAMP和DAMP的致病作用。此外，我们还有更多的证据表明CD13参与了细胞表面受体的再循环。为了在体内模拟这一过程，我们对野生型和CD13缺失的动物进行了永久性股动脉解剖，这会释放TLR4认为是抑制的内源性配体。在功能上，CD13缺失的小鼠的行走和血流恢复明显受损，与受损的愈合一致的更多的坏死。此外，缺血肌肉中的细胞因子谱显示，与我们的体外数据以及PAMPs或DAMPS激活TLR4导致夸大病理的研究相一致，表明CD13调节髓系细胞中促炎症和产生干扰素的信号转导之间的平衡。此外，骨髓移植研究表明，CD13缺失的供者造血细胞无法挽救野生型缺血肌肉的灌流和功能，验证了这一观点，并强调了充分了解这一新型调节因子的机制基础的重要性。最后，虽然 显然，先天免疫反应中的单个髓系细胞亚群协调着愈合过程中的后续步骤，它们的相对贡献和具体作用在很大程度上是未知的。与这一建议相关的是，巨噬细胞和DC TLR4信号通过细胞表面和内吞机制发生，支持离散的调控过程，并在不同的细胞类型中对这些基本上未知的途径发挥特定的作用。因此，通过其对内吞作用的调节，我们提出髓系CD13是先天免疫的功能调节器，剖析表达在泛髓系(lysM-cre)和树突状细胞(CD11c-cre)上的CD13在这些调节过程中的相对作用将明显增加我们对髓系细胞对缺血反应的理解，这些信息对于通过操纵这一新靶点来调控愈合的策略的设计至关重要。

项目成果

CD13 regulation of membrane recycling: implications for cancer dissemination.

CD13 膜回收调节：对癌症传播的影响。

• DOI: 10.1080/23723556.2019.1648024
• 发表时间: 2019
• 期刊: Molecular & cellular oncology
• 影响因子: 2.1
• 作者: Ghosh,Mallika;Shapiro,LindaH
• 通讯作者: Shapiro,LindaH

A novel urinary biomarker protein panel to identify children with ureteropelvic junction obstruction - A pilot study.

• DOI: 10.1016/j.jpurol.2020.05.163
• 发表时间: 2020-08
• 期刊: Journal of pediatric urology
• 影响因子: 2
• 作者: Devarakonda CKV;Shearier ER;Hu C;Grady J;Balsbaugh JL;Makari JH;Ferrer FA;Shapiro LH
• 通讯作者: Shapiro LH