Innate immune responses in keratinocytes during viral skin infections

病毒皮肤感染期间角质形成细胞的先天免疫反应

• 批准号: 8728377
• 负责人: LISELOTTE E JENSEN
• 金额: $ 36.46万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-06 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8728377
• 关键词: Adaptor Signaling Protein; Affect; Antiviral Agents; Apoptosis; Bacterial Infections; Biological; Biological Process; Bulla; Caspase-1; Cell Death; Cells; Characteristics; Child; Chronic; DTR gene; Data; Development; Disease; Disease Outbreaks; Disease remission; Drosophila pros protein; Eczema; Effectiveness; Epithelial Cells; Evaluation; Event; Future; Gene Expression; Genes; Government; Healed; Health; Herpesvirus 1; Human; Imiquimod; Immune response; In Vitro; Infection; Infectious Skin Diseases; Inflammation; Inflammatory; Interleukin-1; Interleukins; Knockout Mice; Knowledge; Lead; Mediating; Membrane; Mucous Membrane; Mus; Myeloid Cells; PTGS2 gene; Pain; Pathway interactions; Patients; Peptide Signal Sequences; Persons; Pharmaceutical Preparations; Physiological; Play; Poly C; Poly I-C; Population; Process; Property; Publishing; Recombinant Interleukins; Recruitment Activity; Reporting; Resolution; Role; Secondary Lesion; Signal Transduction; Simplexvirus; Skin; Staging; Stream; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; United States; Viral; Virus; Virus Diseases; Wild Type Mouse; Wound Healing; alternative treatment; cell type; cytokine; cytotoxic; drug development; extracellular; healing; immune function; improved; in vivo; in vivo Model; insight; keratinocyte; latent infection; loss of function; mouse model; novel; novel therapeutic intervention; novel therapeutics; pathogen; programs; public health relevance; receptor; skin lesion

DESCRIPTION (provided by applicant): Herpes simplex virus-1 is a common human viral pathogen that causes incurable latent infections. During active disease the virus replicates in epithelial cells in the skin or mucosa leading to cell death and blistering. Keratinocytes are the primary cell type infected by HSV-1 in the skin and understanding how these cells die and contribute to initiating immune responses and wound healing is important for the development of new therapeutic strategies. This project will generate new insight into these processes by examining how interleukin(IL)-36 and IL-1 function and are released from cells. IL-36 represents three novel cytokines, IL-36?, IL-36? and IL-36? of unknown physiological function related to the classical pro-inflammatory IL-1. Our published and unpublished data indicate that IL-36? is the predominant form of IL-36 expressed in skin. Polyinosinic-polycytidylic acid (poly(I:C)) and imiquimod are two immune response modifiers which have shown promise as new alternative treatments for HSV infections. We recently reported that poly(I:C) induces pyroptosis, a form of pro-inflammatory caspase-1 dependent cell death, in keratinocytes. We further showed for the first time that the leaderless IL-36? was released from the cells as they underwent pyroptosis. These observations, and additional new unpublished data, lead us to hypothesize that IL-36? and pyroptosis are involved in one, or more, host-responses during HSV-1 infections and that therapeutic agents such as poly(I:C) and imiquimod act, at least in part, through these mechanisms. Using a mouse model of active HSV-1 skin infections and IL-36 knockout (KO) mice we found that IL-36?, but not IL-36?, deficient mice developed secondary lesions earlier than wild type mice. Furthermore, skin lesions healed poorly in IL-36? KO mice when these mice were challenged with HSV-1 or poly(I:C). In vivo and in vitro administration of recombinant IL-36? stimulated keratinocyte hyperproliferation and promoted wound healing. IL-36? regulated a subset of the genes induced by IL-1? suggesting that while IL-1? has both pro-inflammatory and wound healing properties the function of IL-36? appears to be more limited towards wound healing. To further characterize the biological activity of IL-36?, in comparison to IL-1?, we will establish mechanisms whereby IL-36? promotes wound healing and distinct gene expression (Aim 1). In Aim 2 we will determine how IL-36? and IL-1? are released from HSV-1 infected cells. Aim 3 will investigate the role(s) of IL-36? and IL-1? and their export mechanisms in mediating therapeutic effects of the immune response modifiers imiquimod and poly(I:C). Completion of these aims will improve our understanding of host-responses in keratinocytes towards HSV-1, including the physiological function of IL-36?. The gained knowledge may explain mechanisms of action of therapeutic agents and will inform future drug development, including IL-36? as a novel wound healing agent.

描述（由申请人提供）：单纯疱疹病毒-1是一种常见的人类病毒病原体，可引起无法治愈的潜伏感染。在活动性疾病期间，病毒在皮肤或粘膜的上皮细胞中复制，导致细胞死亡和起泡。角质形成细胞是皮肤中被HSV-1感染的主要细胞类型，了解这些细胞如何死亡并促进启动免疫反应和伤口愈合对于开发新的治疗策略非常重要。该项目将通过研究白细胞介素(IL)-36和IL-1如何发挥作用并从细胞中释放出来，对这些过程产生新的见解。IL-36代表三种新的细胞因子，IL-36？, IL-36 ?和IL-36吗?与经典的促炎IL-1相关的未知生理功能。我们已发表和未发表的数据表明IL-36？是IL-36在皮肤中表达的主要形式。多肌苷-多胞苷酸（聚（I:C））和咪喹莫特是两种免疫反应调节剂，有望成为HSV感染的新替代治疗方法。我们最近报道了poly（I:C）诱导角化细胞焦亡，一种促炎caspase-1依赖性细胞死亡的形式。我们首次进一步证明了无领导IL-36？在细胞热亡过程中被释放出来。这些观察结果，以及其他新的未发表的数据，使我们假设IL-36？在1型单纯疱疹病毒感染期间，热亡参与一种或多种宿主反应，聚（I:C）和咪喹莫特等治疗剂至少部分通过这些机制起作用。利用活动性HSV-1皮肤感染和IL-36敲除（KO）小鼠模型，我们发现IL-36？但IL-36没有？缺陷小鼠比野生型小鼠更早出现继发性病变。此外，IL-36？当这些小鼠被HSV-1或poly（I:C）攻击时。体内和体外给药重组IL-36？刺激角质细胞增生，促进伤口愈合。IL-36吗?调节IL-1诱导的基因子集？这表明IL-1？IL-36具有促炎和伤口愈合的功能？似乎更局限于伤口愈合。进一步表征IL-36的生物活性？与IL-1相比？，我们会建立机制，让IL-36？促进伤口愈合和独特的基因表达（目的1）。在Aim 2中，我们将确定IL-36？和il - 1 ?从1型单纯疱疹病毒感染的细胞中释放出来目的3将研究IL-36的作用。和il - 1 ?及其在免疫反应调节剂咪喹莫特和聚（I:C）介导治疗效果中的输出机制。这些目标的完成将提高我们对角化细胞对HSV-1的宿主反应的理解，包括IL-36的生理功能。获得的知识可以解释治疗药物的作用机制，并将为未来的药物开发提供信息，包括IL-36？作为一种新型的伤口愈合剂。

项目成果

Interleukin-1α released from HSV-1-infected keratinocytes acts as a functional alarmin in the skin.

• DOI: 10.1038/ncomms6230
• 发表时间: 2014-10-17
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Milora, Katelynn A.;Miller, Samantha L.;Sanmiguel, Julio C.;Jensen, Liselotte E.
• 通讯作者: Jensen, Liselotte E.

Imiquimod Treatment Causes Systemic Disease in Mice Resembling Generalized Pustular Psoriasis in an IL-1 and IL-36 Dependent Manner.

• DOI: 10.1155/2016/6756138
• 发表时间: 2016
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Alvarez P;Jensen LE
• 通讯作者: Jensen LE

Interleukin-36β provides protection against HSV-1 infection, but does not modulate initiation of adaptive immune responses.

• DOI: 10.1038/s41598-017-05363-4
• 发表时间: 2017-07-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Milora KA;Uppalapati SR;Sanmiguel JC;Zou W;Jensen LE
• 通讯作者: Jensen LE