IRF6 in the Inflammatory Phase of Cutaneous Wound Healing

皮肤伤口愈合炎症阶段的 IRF6

• 批准号: 8288437
• 负责人: MARTINE DUNNWALD
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF IOWA
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8288437
• 关键词: Affect; Autoimmune Diseases; Biological Assay; Biology; Candida albicans; Cell physiology; Cells; Chemotaxis; Chronic; Chronic Obstructive Airway Disease; Cleaved cell; Clinical; Cutaneous; Data; Diabetes Mellitus; Disease; Epidermis; Excision; Family; Family member; Functional disorder; Goals; Granulation Tissue; Healed; Health; Human; Image; Immune; Immune response; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interferons; Intervention; Knock-out; Knockout Mice; Knowledge; Laboratories; Life; Limb structure; Malignant Neoplasms; Measures; Migration Assay; Modeling; Morphogenesis; Muramidase; Mus; Mutation; Myelogenous; Natural Immunity; Neonatal; Neonatal Mortality; Operative Surgical Procedures; Pathway interactions; Patients; Peritoneal Macrophages; Peritonitis; Phase; Phosphorylation; Positioning Attribute; Process; Production; Public Health; Role; Serum; Signal Transduction; Skin; Stimulus; Syndrome; Testing; Van der Woude syndrome; Work; Wound Healing; cost; craniofacial; cytokine; healing; improved; in vivo; indexing; innovation; interest; keratinocyte; macrophage; member; migration; mouse model; neutrophil; orofacial; recombinase; response; tissue repair; transcription factor; wound

DESCRIPTION (provided by applicant): The innate immune system is of critical importance in the initiation of the inflammation and proper wound healing. Amongst molecules modulating the immune response are the transcription factors of the interferon regulatory factor (IRF) family. Of particular interest is IRF6, a unique member of this family and a transcriptional regulator of wound healing. Indeed, patients with Van der Woude syndrome (VWS), an autosomal dominant orofacial clefting syndrome caused by IRF6 haploinsufficiency, are more likely to have wound complications following corrective surgery than patients with a non-syndromic form of orofacial clefting. Loss of Irf6 results in craniofacial, limb and epidermal anomalies in the mouse, leading to neonatal mortality. We recently identified the presence of strong Irf6 signal in the granulation tissue of excisional wounds, particularly in macrophages and neutrophils. Preliminary data show that neutrophils from patients with VWS have impaired chemotaxis in vitro compared to controls. Furthermore, conditional removal of Irf6 in neutrophils and macrophages in a unique murine model results in a three fold reduction of cellular influx in a simple model of inflammation. Finally, cutaneous wound healing was severely impaired seven days post-wounding. Although the function of other IRF family members in innate immunity is well described, nothing is known about the function of IRF6 in innate immune cells and how it affects the inflammatory phase of cutaneous wound healing. The central hypothesis of this proposal is that Irf6 is required for proper macrophages and neutrophils function in vitro and in vivo in the context of wound healing. In specific aim #1, we will test the hypothesis that Irf6 regulates the secretion and migration of macrophages and neutrophils using luminex assay and live imaging of migration assays. In specific aim #2, we will directly test the hypothesis that expression of Irf6 in innate immune cells is necessary for the proper inflammatory phase of wound healing using our Irf6-conditional knockout mouse crossed with a lysosyme-driven Cre-recombinase mouse model. This proposal is innovative in that it extends the recently discovered role of Irf6 in epidermal morphogenesis and biology to innate immunity and cutaneous wound healing-a process that is highly significant from a clinical perspective, and a major cause of rising health-related costs. A the completion of these studies, we will have a better understanding of the contribution of Irf6 to the inflammatory process during cutaneous wound healing. Because continuous inflammation is a phenomenon leading to chronic wounds, chronic obstructive pulmonary disease, and is also implicated in cancer, new information will be obtained about a potential pathophysiological mechanism for these other common health concerns. PUBLIC HEALTH RELEVANCE: Relevance to Public Health This proposal will evaluate the role of Interferon Regulatory Factor 6 in inflammation in the context of cutaneous wound healing, a major cause of rising health-related costs. We expect to better understand how body closes holes and forms seams following injury. This work could have application to any inflammatory disease, including diabetes, autoimmune disorders, chronic wounds and cancer.

描述（由申请人提供）：先天免疫系统对于炎症和适当的伤口愈合至关重要。调节免疫反应的分子中，干扰素调节因子（IRF）家族的转录因子。特别值得关注的是IRF6，这是该家族的独特成员，也是伤口愈合的转录调节剂。实际上，与患有非同伴形式的口腔裂裂矫正手术的患者相比，由IRF6单倍症引起的范德沃德综合征（VWS）的患者是由IRF6单倍症引起的常染色体显性质裂综合征。 IRF6的丧失导致小鼠中的颅面，肢体和表皮异常，导致新生儿死亡率。我们最近确定了颗粒中存在强IRF6信号 切除伤口的组织，特别是在巨噬细胞和中性粒细胞中。初步数据表明，与对照组相比，来自VWS患者的中性粒细胞在体外趋化性障碍。此外，在独特的鼠模型中，有条件地去除中性粒细胞和巨噬细胞中的IRF6导致在简单的炎症模型中降低了细胞涌入的三倍。最后，围场七天，皮肤伤口愈合严重受损。尽管其他IRF家族成员在先天免疫中的功能得到了很好的描述，但对IRF6先天免疫细胞的功能及其如何影响皮肤伤口愈合的炎症阶段尚无。 该提议的中心假设是，在伤口愈合的背景下，适当的巨噬细胞和中性粒细胞在体外和体内起作用是必需的。在特定的目标＃1中，我们将检验以下假设：IRF6使用Luminex分析和迁移分析的实时成像调节巨噬细胞和中性粒细胞的分泌和迁移。在特定的目标＃2中，我们将直接检验以下假设：使用我们的IRF6 - 条件敲除小鼠与溶酶体驱动的Cre-Recombinase小鼠模型交叉的IRF6-条件敲除小鼠，对先天免疫细胞中的IRF6表达对于伤口愈合的适当炎症阶段是必需的。 该提案具有创新性，因为它扩展了IRF6在表皮形态发生和生物学中的最近发现的作用到先天免疫和皮肤伤口愈合 - 从临床角度来看，这是高度重要的，这是与健康相关成本上升的主要原因。 a这些研究的完成，我们将更好地了解IRF6对 皮肤伤口愈合过程中的炎症过程。由于连续炎症是导致慢性伤口，慢性阻塞性肺部疾病的一种现象，并且还与癌症有关，因此将获得有关这些其他常见健康问题的潜在病理生理机制的新信息。 公共卫生相关性：与公共卫生相关性，该提案将评估干扰素调节因素6在皮肤伤口愈合的背景下炎症中的作用，这是与健康相关成本上升的主要原因。我们希望更好地理解身体如何关闭孔和形成受伤后的接缝。这项工作可以应用于任何炎症性疾病，包括糖尿病，自身免疫性疾病，慢性伤口和癌症。