Cytosolic DNA sensors in cutaneous wound healing and host defense

摘要 皮肤先天免疫系统是抵御病原微生物的第一道防线，也是 在治愈受伤的皮肤方面起着关键作用。模式识别受体(PRR)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Pamps和Dumps)。虽然Toll样受体很早就被认为可以触发 胞外和胞内PAMPs和DAMPS、胞浆核酸对免疫细胞的激活作用 传感器正在成为皮肤免疫介导性疾病的主要调节器。这些胞液传感器 包括胞液DNA传感器，可以识别内源和外源DNA和RNA物种。在……里面 事实上，Toll样受体3(TLR3)对dsRNA的识别被证明会影响紫外线辐射诱导的皮肤 损伤，并调节受伤后的皮肤再生。DNA在细胞中的识别 胞浆对皮肤免疫的调节作用知之甚少。两个主要的胞质DNA传感器系统触发 大多数细胞信号事件。干扰素基因的环状GMP-AMP合成酶和刺激物 (cGAS-STING)途径导致I型干扰素(IFN)的有效诱导，并已被证明参与其中 在狼疮和狼疮样疾病中。另一个细胞质DNA传感器，在黑色素瘤2(AIM2)中缺失，激活 AIM2炎症体诱导白介素1β(IL-1β)和IL-18，并被证明与银屑病有关 发病机制。虽然这些通路在炎症性皮肤病中被异常诱导，但这些通路是如何 对正常皮肤免疫力的影响还知之甚少。我们最近发现金黄色葡萄球菌 通过激活cGAS-STING通路诱导I型干扰素并限制 IL-1β。我们假设cGAS-STING和AIM2通路对皮肤免疫有不同的调节作用 在金黄色葡萄球菌感染后和伤口愈合期间。在目标1中，我们将测试AIM2的假设 炎症小体是皮肤IL-1β产生和中性粒细胞募集的主要调节因子，在 皮肤金黄色葡萄球菌感染后的宿主防御作用。在目标2中，我们将检验这两个假设 胞浆DNA通路在创伤愈合过程中的作用与cGAS-Sting-干扰素的激活相反 促进伤口愈合和组织再生的途径，以及激活AIM2导致更多 炎症，伤口愈合不良，组织再生受损。这里描述的实验将 提供靶向胞浆DNA感受器通路是否可导致创面新治疗的证据 对微生物的治愈或保护。

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.