Eosinophil:M2 Macrophage:CCL11 Axis in Experimental Colitis and Pediatric Cortico

实验性结肠炎和小儿皮质中的嗜酸性粒细胞：M2 巨噬细胞：CCL11 轴

• 批准号: 8451994
• 负责人: SIMON Patrick HOGAN
• 金额: $ 32.11万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451994
• 关键词: 17q12; Adrenal Cortex Hormones; Adult; Affect; Anti-Tumor Necrosis Factor Therapy; Biological Assay; Biological Markers; Biopsy; Bone Marrow; CCL11 gene; Calcium-Binding Proteins; Chemotaxis; Child; Childhood; Clinical; Colectomy; Colitis; Colon; Crohn' s disease; Data; Dependency; Diagnosis; Disease; Disease remission; Disease susceptibility; Eosinophilia; Europe; Exposure to; Genes; Goals; Growth; Healed; Histologic; Histopathology; Human; ITGAM gene; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Leukocyte L1 Antigen Complex; Leukocytes; Ligands; Link; Maintenance Therapy; Mediating; Medical; Mesalamine; Modeling; Molecular Weight; Movement; Mus; Natural Immunity; Non-Steroidal Anti-Inflammatory Agents; North America; Operative Surgical Procedures; Organ Culture Techniques; Outcome Study; Pathway interactions; Patients; Population; Predictive Value; Prognostic Marker; Quality of life; Refractory; Refractory Disease; Regulation; Relapse; Relative (related person); Resistance; Role; S100 Proteins; S100A8 gene; S100A9 gene; Severities; Sodium Dextran Sulfate; Source; Steroids; Testing; Therapeutic Agents; Time; Tissues; Ulcerative Colitis; Up-Regulation; aggressive therapy; base; cohort; early onset; eosinophil; eosinophil peroxidase; eosinophilic inflammation; follow-up; healing; improved; indexing; macrophage; monocyte; p65; prospective; receptor for advanced glycation endproducts; research study; thiopurine; treatment response

DESCRIPTION (provided by applicant): Corticosteriods (CS) remains the mainstay of therapy for pediatric UC; however, 20% of patients fail to respond to CS therapy and require secondary-line therapies and escalation of medical management or colectomy4. In recent patient-based studies, we demonstrated that CCL11 levels correlated with tissue eosinophil numbers, which, in turn, correlated with the UC Histologic Index of Severity (UCHIS) in pediatric UC. In preliminary studies, we determined that high rectosigmoid eosinophil levels at the time of pediatric UC diagnosis is linked with reduced likelihood of achieving steroid-free remission (SFR). Notably, high eosinophil levels positively correlated with levels of CCL11 and a low molecular weight intracellular calcium binding protein called calprotectin. In experimental studies, we have identified a link between calprotectin, M¿-derived CCL11, and eosinophils in experimental colitis. Importantly, we show that colonic M¿s express the calprotectin receptor (RAGE); and calprotectin stimulates p65 activation and CCL11 expression in M¿s in vitro. The object of this application is to further understand the relative contribution of calprotectin to inflammatory M¿-derived CCL11 and eosinophilic inflammation in experimental colitis and pediatric UC and treatment responses. Our central hypothesis is that calprotectin-induced activation of M¿s regulates CCL11-dependent colonic eosinophilic inflammation in experimental colitis and pediatric UC and that this pathway drives refractory disease. We will test this hypothesis by examining the relationship between calprotectin, M¿s, CCL11, and eosinophils in pediatric UC at diagnosis and the relationship of this pathway to refractory disease. We will employ S100A9-/-, RAGE-/-, CCR2-/-, CCR2-/-/Il10-/- mice; use DSS- and NSAID-induced Il10-/- models of colitis; generate bone marrow-derived M¿-specific chimeric mice and perform eosinophil chemotaxis assays to define M¿-derived CCL11 in eosinophil recruitment and histopathology in experimental colitis and the sensitivity of this pathway to CS treatment. With respect to expected outcomes, the studies proposed in Aim I are expected to define the association between calprotecin, CCL11+ M¿s, and eosinophils in pediatric UC; the sensitivity of this pathway to CS; and the predictive value of CCL11 and eosinophils disease as an indicator of resistance to first-line therapies. Aim II is expected to delineate colonic eosinophilc inflammation and histopathology dependency on calprotectin/RAGE-induced M¿-derived CCL11 in experimental colitis. Aim III is expected to define the capacity of calprotectin/RAGE to induce M¿-derived CCL11 and eosinophil chemotaxis and sensitivity to CS-induced inhibition. Demonstration of calprotectin/M¿/CCL11/eosinophil axis involvement in resistance to first-line therapies in pediatric UC will have important clinical implications for both the usage of CCL11 and eosinophils as a prognostic indicator for resistance to first-line therapies at diagnosis and the possible usage of therapeutic agents targeting eosinophils and eosinophil regulatory molecules as an approach for improved treatment of pediatric UC and refractory UC.

描述（由适用提供）：Corticosteriods（CS）仍然是小儿UC治疗的支柱；但是，有20％的患者无法对CS疗法做出反应，需要二线疗法和医疗管理或收集术的升级4。在最近的基于患者的研究中，我们证明了CCL11水平与组织嗜酸性粒细胞数量相关，这反过来又与小儿UC中的UC组织学指数（UCHIS）相关。在初步研究中，我们确定小儿UC诊断时高的直形性嗜酸性粒细胞水平与实现无立体声缓解（SFR）的可能性降低有关。值得注意的是，高嗜酸性粒细胞水平与CCL11水平和低分子量的细胞内钙结合蛋白（称为钙染色素）正相关。在实验研究中，我们已经确定了钙骨蛋白钙蛋白钙钙蛋白酶素，衍生的CCL11和嗜酸性粒细胞之间的联系。重要的是，我们表明结肠m表达钙摆素受体（RAGE）；钙染色素在体外刺激p65激活和CCL11表达。该应用的目的是进一步了解钙染色素对实验性结肠炎和小儿UC和治疗反​​应中炎症性M源性CCL11和嗜酸性感染的相对贡献。我们的核心假设是，钙染色素诱导的M的激活调节实验性结肠炎和小儿UC中CCL11依赖性的结肠嗜酸性感染，并且该途径驱动耐火性疾病。我们将通过研究诊断时小儿UC中的钙染色素，m s，ccl11和嗜酸性粒细胞之间的关系来检验这一假设，以及这种途径与难治性疾病的关系。我们将使用S100A9 - / - ，愤怒 - / - ，CCR2 - / - ，CCR2 - / - / - /IL10 - / - 小鼠；使用DSS和NSAID诱导的结肠炎的IL10 - / - 模型；产生骨髓衍生的M€特异性嵌合小鼠，并进行嗜酸性趋化性分析，以在实验性结肠炎中定义M衍生的CCL11，并在嗜酸性粒细胞募集和组织病理学中定义了这种途径对CS治疗的敏感性。关于预期的结果，预计目标I在目标I中提出的研究将定义儿科UC中钙蛋白钙蛋白石，CCL11+ M s和嗜酸性粒细胞之间的关联。该途径对CS的敏感性； CCL11和嗜酸性粒细胞疾病的预测价值是对一线疗法的抗性的指标。 AIM II有望描绘实验性结肠炎中对钙染色素/rage诱导的M衍生的CCL11的结肠嗜酸性注射和组织病理学的依赖性。预计AIM III将定义钙骨/愤怒诱导M？衍生的CCL11和嗜酸性粒细胞趋化性的能力，以及对CS诱导的抑制的敏感性。钙抗蛋白/m¿/cCl11/嗜酸性粒细胞轴参与对小儿UC的一线疗法的参与将具有重要的临床意义分子作为改善小儿UC和难治性UC治疗的方法。