Impact of versican deficiency on the innate immune response to influenza virus

多功能蛋白聚糖缺陷对流感病毒先天免疫反应的影响

• 批准号: 10308382
• 负责人: William A Altemeier
• 金额: $ 61.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-12 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308382
• 关键词: Address; Adhesions; Agonist; Anti-Inflammatory Agents; Bacteria; Biological; Cause of Death; Cell Culture Techniques; Cells; Chemotaxis; Chondroitin Sulfate A; Chondroitin Sulfate Proteoglycan; Cues; Data; Development; Embryonic Development; Exposure to; Extracellular Matrix; Fibroblasts; Generations; Genes; Genetically Engineered Mouse; Glycosaminoglycans; Immune response; In Vitro; Infection; Inflammatory; Innate Immune Response; Interferon Type I; Interferons; Interleukin-10; Laboratories; Leukocytes; Liquid substance; Lung; Lung infections; Modeling; Mus; Natural Immunity; Pathway interactions; Phenotype; Poly C; Poly I-C; Population; Production; Property; Proteoglycan; Public Health; Publishing; Pulmonary Inflammation; Recovery; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Source; Specificity; Stromal Cells; Structure of parenchyma of lung; TCF Transcription Factor; Testing; Therapeutic; Time; Toll-like receptors; United States; Viral; Virus; Work; beta catenin; cell type; chemokine; cytokine; design; extracellular; immunoregulation; improved; influenzavirus; macrophage; migration; mouse model; novel; response; transcription factor; type I interferon receptor; versican

PROJECT SUMMARY Our published work and preliminary data using mouse models and in vitro cell cultures show that extracellular matrix (ECM) molecules such as versican accumulate in lungs following exposure to viruses and bacteria. The creation of a specialized versican-enriched ECM coincides with invasion and retention of leukocytes in lungs during the immune response to influenza virus. We have found that two cellular sources synthesize versican in response to Toll-like receptor (TLR) agonists: macrophages and fibroblasts. Studies identify two distinct signaling pathways directing versican synthesis in these two cell types - the β-catenin/T-cell factor (TCF) pathway in stromal cells such as smooth muscle cells and fibroblasts and the TLR/Trif/Type I interferon (IFN) receptor pathway in macrophages. However, the cellular specificity of these signaling pathways is not known. Using two novel strains of genetically engineered mice in which the versican gene is deleted in a cell- and time-specific manner, our published and preliminary data shows that versican has a dramatic effect on leukocyte phenotype. When treated with polyinosinic:polycytidylic acid (poly(I:C)), mice with a global deficiency in versican have decreased recovery of leukocytes in bronchoalveolar (BAL) fluid suggesting that versican is pro-inflammatory and required for leukocyte migration into lungs. In contrast, mice lacking versican in macrophages have increased recovery of leukocytes in BAL fluid suggesting that macrophage-derived versican is anti- inflammatory and suppresses leukocyte migration into lungs. Both strains of versican-deficient mice had significantly decreased recovery of Type I IFNs and IL-10 in lung tissue or BAL fluid when compared to controls. Our in vitro studies attribute this to decreased production of these anti-inflammatory cytokines by versican-deficient macrophages. The differences observed in these novel versican-deficient mice are the basis of our central hypothesis that the formation of a versican-enriched ECM by macrophages and stromal cells provides critical contextual cues and extracellular-control of the innate immune response to viral lung infection. We propose three aims to test this hypothesis. Aim 1 defines the role of versican derived from macrophages and/or Type I IFN signaling in providing extracellular-control of the innate immune response in lungs of mice exposed to influenza virus. Aim 2 determines if stromal cells and/or β- catenin/TCF signaling promote the generation of a versican-enriched ECM that provides fine-control of the innate immune response to influenza virus. Aim 3 identifies the mechanisms and signaling pathways whereby macrophage- versus fibroblast-derived versican provide contextual extracellular-control of the innate immune response. Understanding the contextual settings in which versican provides fine-control of the innate immune response to influenza virus is critical for the design of therapeutic strategies for improving the immune response to viral lung infection.

项目总结

项目成果

Regulation of Versican Expression in Macrophages is Mediated by Canonical Type I Interferon Signaling via ISGF3.

巨噬细胞中多功能蛋白聚糖表达的调节是由典型的 I 型干扰素信号通过 ISGF3 介导的。

• DOI: 10.1101/2024.03.14.585097
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Chang,MaryY;Chan,ChristinaK;Brune,JourdanE;Manicone,AnneM;Bomsztyk,Karol;Frevert,CharlesW;Altemeier,WilliamA
• 通讯作者: Altemeier,WilliamA

The Translational Value of Rodent Models of Sepsis.

脓毒症啮齿动物模型的转化价值。

• DOI: 10.1164/rccm.202308-1489vp
• 发表时间: 2024
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Matthay,MichaelA;Schmidt,EricP;Bastarache,JulieA;Calfee,CarolynS;Frevert,CharlesW;Martin,ThomasR
• 通讯作者: Martin,ThomasR

Multicompartmental analysis of the murine pulmonary immune response by spectral flow cytometry.

• DOI: 10.1152/ajplung.00317.2022
• 发表时间: 2023-10-01
• 期刊: American journal of physiology. Lung cellular and molecular physiology

Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen.

分泌的 PLA2 X 组协调对吸入过敏原的先天和适应性免疫反应。

• DOI: 10.1172/jci.insight.94929
• 发表时间: 2017
• 期刊: JCI insight
• 影响因子: 8
• 作者: Nolin,JamesD;Lai,Ying;Ogden,HerbertLuke;Manicone,AnneM;Murphy,RyanC;An,Dowon;Frevert,CharlesW;Ghomashchi,Farideh;Naika,GajendraS;Gelb,MichaelH;Gauvreau,GailM;Piliponsky,AdrianM;Altemeier,WilliamA;Hallstrand,TealS
• 通讯作者: Hallstrand,TealS

Revisiting the scientific method to improve rigor and reproducibility of immunohistochemistry in reproductive science.

重新审视提高生殖科学中免疫组织化学的严谨性和重现性的科学方法。

• DOI: 10.1093/biolre/ioy094
• 发表时间: 2018
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Manuel,SharrónL;Johnson,BrianW;Frevert,CharlesW;Duncan,FrancescaE
• 通讯作者: Duncan,FrancescaE