Cytosolic DNA sensors in cutaneous wound healing and host defense

细胞质 DNA 传感器在皮肤伤口愈合和宿主防御中的作用

• 批准号: 9761443
• 负责人: PHILIP SCUMPIA
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-09 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761443
• 关键词: AIM2 gene; Adenine; Affect; Agonist; Anti-Infective Agents; Antiviral Agents; Antiviral Response; Biological Response Modifiers; Cells; Cutaneous; Cyclic GMP; Cytosol; DNA; Data; Disease; Disease Pathway; Double-Stranded RNA; Event; Excision; Gene Activation; Genes; Genetic Transcription; Guanosine; Host Defense; Immune; Immune Cell Activation; Immune response; Immunity; Impaired wound healing; Impairment; Infection; Infectious Skin Diseases; Inflammasome; Inflammation; Inflammatory; Injury; Innate Immune System; Interferon Type I; Interferons; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Interleukin-18; Interleukins; Knowledge; Lead; Ligands; Mediating; Modeling; Molecular; Mus; Natural regeneration; Neutrophil Infiltration; Nucleic Acids; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Pattern recognition receptor; Periodicity; Play; Process; Production; Psoriasis; RNA; Role; Signal Transduction; Skin; Splint Device; Staphylococcus aureus; Staphylococcus aureus infection; Stimulator of Interferon Genes; Surgical incisions; System; TLR3 gene; Tensile Strength; Testing; Therapeutic; Tissues; Toll-like receptors; UV induced; Work; Wound Healing; ds-DNA; experimental study; extracellular; healing; improved; injured; insight; lupus-like; microbial; microorganism; neutrophil; novel; novel therapeutics; pathogen; public health relevance; receptor; repaired; response; sensor; skin barrier; skin disorder; small molecule; tissue regeneration; transcriptome sequencing; wound; wound closure

ABSTRACT The cutaneous innate immune system is the first line of defense against pathogenic microorganisms, but also plays a key role in healing injured skin. Pattern recognition receptors (PRRs) orchestrate the molecular and cellular events that occur following the recognition of pathogen or danger associated molecular patterns (PAMPs and DAMPs, respectively) in the skin. While Toll-like receptors have long been known to trigger immune cell activation in response to extracellular and endosomal PAMPs and DAMPs, cytosolic nucleic acid sensors are emerging as major regulators of immune mediated diseases in the skin. These cytosolic sensors include cytosolic DNA sensors that can recognize both endogenous and exogenous DNA and RNA species. In fact, recognition of dsRNA by Toll-like receptor 3 (TLR3) was shown to affect UV-radiation induced skin damage, and regulate cutaneous regeneration following wounding. Whether the recognition of DNA in the cytosol regulates cutaneous immunity is poorly understood. Two major cytosolic DNA sensor systems trigger the majority of cellular signaling events. The cyclic GMP-AMP synthase and Stimulator of Interferon Genes (cGAS-STING) pathway results in potent induction of type I interferon (IFN), and has been shown to participate in lupus and lupus-like disease. The other cytosolic DNA sensor, absent in melanoma 2 (AIM2), activates the AIM2 inflammasome to induce interleukin 1β (IL-1β) and IL-18 and was shown to be involved in psoriasis pathogenesis. While these pathways are aberrantly induced in inflammatory skin disease, how these pathways contribute to normal cutaneous immunity is less understood. We recently showed that Staphylococcus aureus subverts cutaneous host defense by activating the cGAS-STING pathway to induce type I interferon and limit IL-1β. We hypothesize that the cGAS-STING and AIM2 pathways differentially regulate cutaneous immunity following S. aureus infection and during wound healing. In Aim 1, we will test the hypothesis that the AIM2 inflammasome is a major regulator of cutaneous IL-1β production and neutrophil recruitment, playing a critical role in host defense following cutaneous S. aureus infection. In Aim 2, we will test the hypothesis that the two cytosolic DNA pathways play opposing roles during wound healing with activation of the cGAS-STING-IFN pathway resulting in improved wound healing and tissue regeneration and activation of AIM2 resulting in more inflammation, poor wound healing, and impaired tissue regeneration. The experiments described herein will provide evidence whether targeting cytosolic DNA sensor pathways can result in new treatments for wound healing or protection against microbial organisms.

摘要 皮肤先天免疫系统是抵御病原微生物的第一道防线， 在修复受伤的皮肤方面起着关键作用。模式识别受体（PRRs）协调分子和 识别病原体或危险相关分子模式后发生的细胞事件 （分别为PAMP和DAMP）。虽然Toll样受体很久以前就被认为可以触发 免疫细胞对细胞外和内体PAMP和DAMP、胞质核酸 传感器正在成为皮肤中免疫介导疾病的主要调节剂。这些胞质传感器 包括能够识别内源性和外源性DNA和RNA种类细胞溶质DNA传感器。在 事实上，Toll样受体3（TLR 3）对dsRNA的识别显示出影响UV辐射诱导的皮肤 损伤，并调节创伤后的皮肤再生。是否识别DNA在 胞质溶胶调节皮肤免疫的机制知之甚少。两种主要的胞质DNA传感器系统触发 大多数细胞信号事件。环GMP-AMP合酶与干扰素基因刺激因子 （cGAS-STING）途径导致I型干扰素（IFN）的有效诱导，并且已经显示参与了IFN-γ的诱导。 狼疮和类似狼疮的疾病。另一个胞质DNA传感器，在黑素瘤2（AIM 2）中不存在，激活了 AIM 2炎性小体诱导白细胞介素1β（IL-1β）和IL-18，并显示参与银屑病 发病机制虽然这些通路在炎症性皮肤病中被异常诱导，但这些通路如何在炎症性皮肤病中发挥作用？ 对正常皮肤免疫力的贡献了解较少。我们最近发现金黄色葡萄球菌 通过激活cGAS-STING途径来诱导I型干扰素并限制免疫，从而破坏宿主的皮肤防御 IL-1β。我们假设cGAS-STING和AIM 2途径差异调节皮肤免疫 继S。金黄色葡萄球菌感染和伤口愈合期间。在目标1中，我们将检验AIM 2 炎性小体是皮肤IL-1β产生和中性粒细胞募集的主要调节剂，在皮肤炎症反应中起关键作用。 在皮肤S.金黄色葡萄球菌感染。在目标2中，我们将检验这两个假设， 在cGAS-STING-IFN激活的伤口愈合过程中，细胞溶质DNA途径发挥相反的作用 导致伤口愈合和组织再生改善的AIM 2途径和导致更多 炎症、伤口愈合不良和组织再生受损。本文所述的实验将 提供了靶向细胞溶质DNA传感器通路是否可以产生新的伤口治疗方法的证据 治愈或保护免受微生物的侵害。