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的引发和适当的伤口愈合至关重要。调节免疫反应的分子包括干扰素调节因子 (IRF) 家族的转录因子。特别令人感兴趣的是 IRF6，它是该家族的独特成员，也是伤口愈合的转录调节因子。事实上，范德沃德综合征 (VWS) 是一种由 IRF6 单倍体不足引起的常染色体显性口颌面裂综合征，与非综合征型口颌面裂患者相比，矫正手术后更容易出现伤口并发症。 Irf6 的缺失会导致小鼠颅面、四肢和表皮异常，从而导致新生儿死亡。我们最近发现颗粒中存在强 Irf6 信号 切除伤口的组织，特别是巨噬细胞和中性粒细胞。初步数据显示，与对照组相比，VWS 患者的中性粒细胞在体外的趋化性受损。此外，在独特的小鼠模型中，有条件地去除中性粒细胞和巨噬细胞中的 Irf6 可使简单炎症模型中的细胞流入减少三倍。最后，受伤后 7 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已得到很好的描述，但对于 IRF6 在先天免疫细胞中的功能以及它如何影响皮肤伤口愈合的炎症阶段，我们一无所知。 该提议的中心假设是，在伤口愈合的情况下，Irf6 是巨噬细胞和中性粒细胞在体外和体内发挥正常功能所必需的。在具体目标#1中，我们将使用 luminex 测定和迁移测定的实时成像来测试 Irf6 调节巨噬细胞和中性粒细胞的分泌和迁移的假设。在具体目标#2中，我们将使用我们的 Irf6 条件敲除小鼠与溶酶体驱动的 Cre 重组酶小鼠模型杂交，直接测试先天免疫细胞中 Irf6 的表达对于伤口愈合的适当炎症阶段所必需的假设。 该提案的创新之处在于，它将最近发现的 Irf6 在表皮形态发生和生物学中的作用扩展到先天免疫和皮肤伤口愈合——从临床角度来看，这一过程非常重要，也是健康相关成本上升的主要原因。完成这些研究后，我们将更好地了解 Irf6 对 皮肤伤口愈合过程中的炎症过程。由于持续炎症是一种导致慢性伤口、慢性阻塞性肺病的现象，并且还与癌症有关，因此我们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。 公共健康相关性：与公共健康的相关性 该提案将评估干扰素调节因子 6 在皮肤伤口愈合炎症中的作用，皮肤伤口愈合是健康相关成本上升的主要原因。我们希望更好地了解身体在受伤后如何闭合孔洞并形成接缝。这项工作可适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。