更新于：2024-05-01

IRF5

interferon regulatory factor 5

更新于：2024-05-01

基本信息

别名

interferon regulatory factor 5、IRF-5、IRF5

简介

Transcription factor that plays a critical role in innate immunity by activating expression of type I interferon (IFN) IFNA and INFB and inflammatory cytokines downstream of endolysosomal toll-like receptors TLR7, TLR8 and TLR9 (PubMed:11303025, PubMed:15695821, PubMed:22412986, PubMed:25326418, PubMed:32433612). Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters (By similarity). Can efficiently activate both the IFN-beta (IFNB) and the IFN-alpha (IFNA) genes and mediate their induction downstream of the TLR-activated, MyD88-dependent pathway (By similarity). Key transcription factor regulating the IFN response during SARS-CoV-2 infection (PubMed:33440148).

关联

项与 IRF5 相关的药物

siIRF5@EINI

靶点

IRF5

作用机制

IRF5调节剂

在研机构

山东大学

原研机构

山东大学

在研适应症

类风湿关节炎

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 IRF5 相关的临床结果

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100 项与 IRF5 相关的转化医学

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0 项与 IRF5 相关的专利（医药）

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1,024

项与 IRF5 相关的文献（医药）

2024-02-15·Cell reports

The IRAK1/IRF5 axis initiates IL-12 response by dendritic cells and control of Toxoplasma gondii infection.

Article

作者: Milton Pereira ; Theresa Ramalho ; Warrison A Andrade ; Danielle F Durso ; Maria C Souza ; Katherine A Fitzgerald ; Douglas T Golenbock ; Neal Silverman ; Ricardo T Gazzinelli

Activation of endosomal Toll-like receptor (TLR) 7, TLR9, and TLR11/12 is a key event in the resistance against the parasite Toxoplasma gondii. Endosomal TLR engagement leads to expression of interleukin (IL)-12 via the myddosome, a protein complex containing MyD88 and IL-1 receptor-associated kinase (IRAK) 4 in addition to IRAK1 or IRAK2. In murine macrophages, IRAK2 is essential for IL-12 production via endosomal TLRs but, surprisingly, Irak2^-/- mice are only slightly susceptible to T. gondii infection, similar to Irak1^-/- mice. Here, we report that upon T. gondii infection IL-12 production by different cell populations requires either IRAK1 or IRAK2, with conventional dendritic cells (DCs) requiring IRAK1 and monocyte-derived DCs (MO-DCs) requiring IRAK2. In both populations, we identify interferon regulatory factor 5 as the main transcription factor driving the myddosome-dependent IL-12 production during T. gondii infection. Consistent with a redundant role of DCs and MO-DCs, mutations that affect IL-12 production in both cell populations show high susceptibility to infection in vivo.

2024-02-08·Neuroscience

Maresin 1 activates LGR6 to alleviate neuroinflammation via the CREB/JMJD3/IRF4 pathway in a rat model of subarachnoid hemorrhage.

Article

作者: Zhenyan Li ; Wen Yuan ; Xian Yang ; Juan Jiang ; Qi-Lei Zhang ; Xiao-Xin Yan ; Yu-Chun Zuo

Neuroinflammation is an early event of brain injury after subarachnoid hemorrhage (SAH). Whether the macrophage mediators in resolving inflammation 1(MaR1) is involved in SAH pathogenesis is unknown. In this study, 205 male Sprague-Dawley rats were subjected to SAH via endovascular perforation in the experimental and control groups. MaR1 was dosed intranasally at 1 hour after SAH, with LGR6 siRNA and KG-501, GSK-J4 administered to determine the signaling pathway. Neurobehavioral, histological and biochemical data were obtained from the animal groups with designated treatments. The results showed: (i) The leucine-rich repeat containing G protein-coupled receptor 6（LGR6） was decreased after SAH and reached to the lowest level at 24h after SAH. Jumonji d3（JMJD3） protein levels tended to increase and peaked at 24h after SAH. LGR6 and JMJD3 expression were co-localized with microglia. (ii) MaR1 administration mitigated short-term neurological deficits, brain edema and long-term neurobehavioral performance after SAH, and attenuated microglial activation and neutrophil infiltration. (iii) Knockdown of LGR6, inhibition of CREB phosphorylation or JMJD3 activity abolished the anti-neuroinflammatory effect of MaR1 on the expression of CREB, CBP, JMJD3, IRF4, IRF5, IL-1β, IL-6 and IL-10, thus prevented microglial activation and neutrophil infiltration. Together, the results show that MaR1 can activate LGR6 and affect CREB/JMJD3/IRF4 signaling to attenuate neuroinflammation after SAH, pointing to a potential pharmacological utility in this disorder.

2024-02-06·ACS omega

Decellularized Placental Sponge: A Platform for Coculture of Mesenchymal Stem Cells/Macrophages to Assess an M2 Phenotype and Osteogenic Differentiation In Vitro and In Vivo.

Article

作者: Zahra Khosrowpour ; Seyed Mahmoud Hashemi ; Samira Mohammadi-Yeganeh ; Sara Simorgh ; Behnaz Sadat Eftekhari ; Peiman Brouki Milan ; Subhas C Kundu ; Mazaher Gholipourmalekabadi

Effective communication between immune and bone-forming cells is crucial for the successful healing of bone defects. This study aimed to assess the potential of a decellularized placental sponge (DPS) as a coculture system for inducing M1/M2 polarization in macrophages and promoting osteogenic differentiation in adipose-derived mesenchymal stem cells (AD-MSCs), both in vitro and in vivo. We prepared the DPS and conducted a comprehensive characterization of its biomechanical properties, antibacterial activity, and biocompatibility. In vitro, we examined the influence of the DPS on the polarization of macrophages cocultured with AD-MSCs through nitric oxide assays, cytokine assays, phagocytosis tests, and real-time polymerase chain reaction (PCR). For in vivo assessment, we utilized micro-CT imaging, histological evaluations, and real-time PCR to determine the impact of the DPS seeded with Wharton's jelly mesenchymal stem cells (WJ-MSCs) on bone regeneration in a calvarial bone defect model. The coculture of AD-MSCs and macrophages on the DPS led to increased production of IL-10, upregulation of CD206, Arg1, and YM1 gene expression, and enhanced phagocytic capacity for apoptotic thymocytes. Concurrently, it reduced the secretion of TNF-α and nitric oxide (NO), downregulated the expression of CD86, NOS2, and IRF5 genes, and decreased macrophage phagocytosis of yeast. These results indicated polarization of macrophages toward an M2-like phenotype. In vivo, the presence of the DPS resulted in enhanced bone formation at the defect site. Immunostaining demonstrated that both the DPS and DPS + WJ-MSC constructs induced macrophage polarization toward an M2 phenotype, as compared to the control defect. In conclusion, this immunomodulatory effect, coupled with its biocompatibility and biomechanical properties resembling natural bone, positions the DPS as an attractive candidate for further exploration in the field of bone tissue engineering and regenerative medicine.

项与 IRF5 相关的新闻（医药）

2024-04-05

·佰傲谷BioValley

肿瘤中的关键炎症通路

J Hematol Oncol.(一) 类花生酸(Eicosanoid)信号通路：二十烷基硫酸酯信号通路在生理过程和病理过程中都起着关键作用，通过类花生酸将炎症与癌症联系起来。二十碳多不饱和脂肪酸(PUFAs)是由20碳多不饱和脂肪酸(PUFAs)氧化而成的具有高度生物活性的衍生物，可通过环氧合酶(COX)、脂氧合酶(LOX)和细胞色素P450途径产生。COX途径产生前列腺素(PGs)和血栓素A(TXs)，而LOX途径则产生白三烯(LTs)和脂氧素(LXs)。COX信号通路COX家族中，COX-2的表达会受到早期炎症(proinflammatory)的上调，并被发现和调控多种肿瘤的进展相关。在炎症反应的早期阶段，COX-2衍生的PG被认为具有促炎功能。前列腺素D2、前列腺素E2、前列腺素F2α、前列腺素I2和血栓素A2是通过COX通路衍生的五种关键 PG。COX/PEG2COX-2/CSK3β信号还和上皮-间充质转化有关，通过抑制GSK3β来促进E-钙粘蛋白、β-连环蛋白和p120连环蛋白的蛋白质稳定性。抑制COX-2可以下调E-钙黏蛋白导致细胞死亡。PGE2通过其两种E-前列腺素受体EP2和EP4提供信号传导来塑造DC功能。EP4调节CD80、CD86、CD83、MHC II等激活标志物上调以及IL-10和IL-23的产生，引导cDC2成熟，促进T细胞扩增，形成抑制性而非促炎性T细胞群富集。PGE2还可能通过E2调节NK细胞合成IFN-γ来诱导免疫抑制，从而促进肿瘤的发生。肿瘤来源的前列腺素E2(PGE2)介导MDSC分化和获得促肿瘤特征。在PGE2暴露期间，EP2/4联合阻断M-MDSCs可防止这些抑制特征的发生。双重 EP2/EP4 PGE2受体拮抗剂增加了肿瘤微环境淋巴细胞浸润，并显着降低了多种肿瘤模型中的疾病负担。前列腺素D2则是COX-2的另一种代谢物，可能在慢性炎症和癌症中发挥双重作用。PGD2与其受体PTGDR2之间的相互作用抑制了胃癌细胞的自我更新，并减弱了胃癌的生长和转移。脂氧合酶(LOX)信号通路LOX通路负责将花生四烯酸代谢为白三烯，包括白三烯A4(LTA4)、LTB4和LTD4等。炎症细胞(包括白细胞、巨噬细胞和肥大细胞)是白三烯的主要来源。抑制LTB4受体可抑制炎症相关肿瘤的进展，LTD4则在肝细胞癌和慢性乙型肝炎患者的循环中上调。LOX途径主要包括5-LOX、12-LOX和15-LOX。5-LOX在上皮性癌和淋巴瘤中高度表达，具有促血管生成和促肿瘤活性。12-LOX通过激活整合素连接的激酶/NF-κB途径来促进肿瘤的生长。而15-LOX的代谢产物被发现能增强肿瘤相关炎症，既有促肿瘤作用又有抗肿瘤作用。另一种由LOX衍生的类花生酸脂毒素(lipoxins， LXs)则具有抗肿瘤作用。在前列腺癌中，LXA4通过抑制METTL3和或FPR2/IRF4途径，以促进巨噬细胞M2样极化。LXA4对炎性巨噬细胞极化的抑制作用与p-NF-κB p65和IRF5活性的下调有关，从而降低了LPS诱导的M1巨噬细胞通过FPR2/IRF5信号通路的表型和功能极化。 J Hematol Oncol.(二)JAK/STAT信号通路STAT3在炎症反应和肿瘤进展中发挥着广泛的作用。多种生长因子和细胞因子参与典型的STAT3通路，调节细胞分化、血管生成和肿瘤形成。IL-6和STAT3是启动肿瘤的肠上皮细胞生存和增殖所必需的。此外，在设计肠道的肿瘤如前列腺癌中，肠道生物失调增加了肠道通透性，肿瘤内的内毒素通过NF-κB/IL 6/STAT3轴促进了肿瘤的进展。Int Immunopharmacol.影响JAK/STAT通路的药物种类复杂，包括植物化学物质、合成药物和生物分子等等。Int Immunopharmacol.(三)金属代谢铁和ROS氧化还原铁代谢失调是肿瘤细胞的一个重要标志，在肿瘤细胞中，恶性肿瘤细胞需要大量的铁来生存和增殖。细胞色素P450酶、一氧化氮合酶、NADPH氧化酶和脂氧合酶等铁依赖性酶参与ROS的产生。同时，谷胱甘肽过氧化物酶GPX4是一种铁死亡的中枢抑制剂，GPX4利用还原性谷胱甘肽将活性的PUFA-PL-OOH还原为非活性和非致死性的PUFA-PL-OH。抑制Gpx4可通过诱导铁性死亡而增强治疗的抗肿瘤效应。十年铁死亡：双向调控与药物开发锌和NF-κB通路锌与许多炎症性细胞因子的产生和信号传递有关。当对应激刺激做出急性反应时，血浆锌浓度迅速下降。人体的锌代谢与ZIP8等锌转运蛋白的活性密切相关。在感染过程中，激活的NF-κB增加ZIP8的表达，ZIP8定位于细胞膜并调节锌的摄取。锌抑制了IKKβ的活性，从而减弱了炎症反应。参考文献：1.Wang M, Chen S, He X, Yuan Y, Wei X. Targeting inflammation as cancer therapy. J Hematol Oncol. 2024 Mar 22;17(1):13. doi: 10.1186/s13045-024-01528-7.2.Balamurugan K,et al.Stabilization of E-cadherin adhesions by COX-2/GSK3β signaling is a targetable pathway in metastatic breast cancer. JCI Insight. 2023 Mar 22;8(6):e156057. doi: 10.1172/jci.insight.156057.3.Cuenca-Escalona J,et al.PGE2-EP4 signaling steers cDC2 maturation toward the induction of suppressive T-cell responses. Eur J Immunol. 2024 Mar;54(3):e2350770. doi: 10.1002/eji.202350770.4.Francica BJ,et al.Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors. Cancer Res Commun. 2023 Aug 8;3(8):1486-1500. doi: 10.1158/2767-9764.CRC-23-0249.5.Yuan J, et al. Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway. Inflammopharmacology. 2022 Apr;30(2):487-498. doi: 10.1007/s10787-022-00942-y.6.Wang Y,et al. Deciphering JAK/STAT signaling pathway: A multifaceted approach to tumorigenesis, progression and therapeutic interventions. Int Immunopharmacol. 2024 Mar 22;131:111846. doi: 10.1016/j.intimp.2024.111846.·····

免疫疗法

2024-03-25

·GlobeNewswire-Health Care

Linkage of Cancer and Lupus in Gliomas Patients

AGOURA HILLS, Calif., March 25, 2024 (GLOBE NEWSWIRE) -- Oncotelic Therapeutics, Inc (OTCQB:OTLC) announced today the peer reviewed publication of Transforming Growth Factor Beta 2 (TGFB2) mRNA Levels, in Conjunction with Interferon-Gamma Receptor Activation of Interferon Regulatory Factor 5 (IRF5) and Expression of CD276/B7-H3, Are Therapeutically Targetable Negative Prognostic Markers in Low-Grade Gliomas: Past, Present, and Future Strategies in the Treatment and Management of Gliomas. Dr. Vuong Trieu, CEO and Chairman of Oncotelic, stated, ”Our R&D team has discovered crosstalk between the TGF-β and IFN signaling pathways, linking gliomas and Systemic Lupus Erythematosus (SLE). This publication has identified IRF5 as a common target for both diseases, opening up a new avenue for combating cancer,” Our findings place IRF5 at the intersection of inflammation and cancer. Understanding the role of IRF5 in both SLE and cancer opens an avenue for targeting IRF5 or its downstream pathways. This could offer new strategies for treating SLE and various cancers by modulating the immune response. The article can be accessed for free online: https://www.mdpi.com/2072-6694/16/6/1202 Abstract: Gliomas develop in the central nervous system from the glial cells that support it. Low-grade gliomas (LGGs) are characterized by a reduced number of immune cells infiltrating the tumor, requiring immune-boosting therapies to release the immunosuppressive environment of the tumor. We conducted a bioinformatics-led study to evaluate the prognostic impact of cell surface receptor markers for tumor-associated macrophages (TAMs) that produce transforming growth factor beta (TGFB) ligands and interferon-gamma receptor activation to maintain the tumor microenvironment in an immunosuppressed state. Detailed investigation of messenger RNA levels and their impact on OS in LGG patients demonstrated that low mRNA levels of a specific TGFB ligand, TGFB2, and the receptor along with the signaling molecules from interferon-gamma receptor activation (IFNGR2, IRF1, IRF5, and STAT1) result in improved survival of LGG patients. LGG patients expressing high levels of TGFB2 and IFNGR2 are over-represented in IDH wild-type tumor samples, suggesting that TGFB2 and IFNGR2 mRNA can be therapeutically targeted in these high-risk patients. Furthermore, demethylation of TFGB2, IFNGR2, IRF1, IRF5, STAT1, and CD276 genes also results in worse survival outcomes, pointing to a molecular mechanism that increases the negative prognostic effects of increased mRNA levels of these target genes. We observed that significant upregulation of mRNA expression levels for three TAM markers, MSR1/CD204, CD86, and CD68, suggested that TGFB2 is pivotal in establishing a pro-tumorigenic TME in gliomas mediated through TAMs. Interestingly, a tumor-associated antigen CD276/B7-H3 mRNA expression increased in tumor tissue, giving further insights into the roles of macrophages and tumor cells in the immunosuppressive TME. Therefore, to improve OS in LGG patients, combination therapies must target TGFB2 and IFN-γ activation (via IRF5 inhibition) or immune therapies targeted against CD276/B7-H3 About Oncotelic Oncotelic (f/k/a Mateon Therapeutics, Inc.), was formed in the State of New York in 1988 as OXiGENE, Inc., was reincorporated in the State of Delaware in 1992, and changed its name to Mateon Therapeutics, Inc. in 2016, and Oncotelic Therapeutics, Inc. in November 2020. Oncotelic is seeking to leverage its deep expertise in oncology drug development to improve treatment outcomes and survival of cancer patients with a special emphasis on rare pediatric cancers. Oncotelic has rare pediatric designation for Diffuse Intrinsic Pontine Glioma (“DIPG” through OT-101) through its 45% joint venture, GMP Biotechnology Limited, melanoma (through CA4P), and Acute Myeloid Leukemia (through OXi 4503). Oncotelic acquired PointR Data Inc. in November 2019 to build an AI driven biotechnology company. Further, Oncotelic acquired AL-101, during the 4th quarter of 2021, for the intranasal delivery of apomorphine. We intend to develop AL-101 for the treatment of Parkinson Disease, erectile dysfunction, female sexual disorder and hypoactive sexual desire disorder. All these ailments have a very large population suffering from them and there is a need for treatments for each. For more information on AL-101, refer to our Annual Report on Form 10-K/A filed with the SEC on April 19, 2023. Oncotelic's Cautionary Note on Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this communication regarding strategy, future operations, future financial position, prospects, plans and objectives of management are forward-looking statements. Words such as "may", "expect", "anticipate" "hope", "vision", "optimism", "design", "exciting", "promising", "will", "conviction", "estimate," "intend," "believe", "quest for a cure of cancer", "innovation-driven", "paradigm-shift", "high scientific merit", "impact potential" and similar expressions are intended to identify forward-looking statements. Forward looking statements contained in this press release include, but are not limited to, statements about future plans related to the operations of the JV, taking the JV into an initial public offering or the success thereof, the progress, timing of clinical development, scope and success of future clinical trials, the reporting of clinical data for the Company’s product candidates and the potential use of the Company's product candidates to treat various cancer indications as well as obtaining required regulatory approval to conduct clinical trials and upon granting of approval by the regulatory agencies, the successful marketing of the products; building and the success of our nanoparticle platform and the related success of launching the platform, the development of the Company’s AI suite including but not limited to AI Chatbots, the public access to the Company’s AI suite, the success of the development of the AI suite or any other AI technologies and whether if any or portion thereof the Company’s AI suite or technologies will be commercialized and launched for sale. Each of these forward-looking statements involves risks and uncertainties, and actual results may differ materially from these forward-looking statements or may not occur at all. Many factors may cause differences between current expectations and actual results, including unexpected safety or efficacy data observed during preclinical or clinical studies, clinical trial site activation or enrollment rates that are lower than expected, changes in expected or existing competition, changes in the regulatory environment, failure of collaborators to support or advance collaborations or product candidates and unexpected litigation or other disputes, taking the Company or its affiliates through initial public offerings. These risks are not exhaustive, the company faces known and unknown risks, including the risk factors described in the Company's Annual Report on Form 10-K/A filed with the SEC on April 19, 2023 and in the company's other periodic filings. Forward-looking statements are based on expectations and assumptions as of the date of this press release. Except as required by law, the company does not assume any obligation to update forward-looking statements contained herein to reflect any change in expectations, whether because of new information, future events, or otherwise. Contact Information: For Oncotelic Therapeutics, Inc.:Investor Relationsir@oncotelic.com

并购免疫疗法

2024-01-26

·生物探索

Science | 上海交大沈南及Carola G. Vinuesa团队揭示自身免疫疾病新的治疗靶点

引言年龄相关的B细胞(ABCs)在感染、衰老和自身免疫过程中积累，有助于狼疮的发病。2024年1月25日，上海交通大学沈南及Carola G. Vinuesa共同通讯在Science 在线发表题为“The transcription factor ZEB2 drives the formation of age-associated B cells”的研究论文，该研究筛选了驱动ABC形成的转录因子，发现锌指E-box binding homeobox 2 (ZEB2)是人类和小鼠ABC体外分化所必需的。在ZEB2单倍体不足的个体和B细胞中缺乏ZEB2的小鼠中，ABC减少。在Toll样受体7 (TLR7)驱动的狼疮小鼠中，ZEB2是ABC形成和自身免疫病理所必需的。ZEB2结合+20 kb的肌细胞增强因子2b (Mef2b)内含子增强子，抑制Mef2b介导的生发中心B细胞分化，促进ABC的形成。ZEB2也针对ABC规范和功能的重要基因，包括Itgax。ZEB2驱动的ABC分化需要JAK-STAT，使用JAK1/3抑制剂治疗可减少自身免疫性小鼠和患者中ABC的积累。因此，ZEB2是B细胞自身免疫的一种驱动因子。年龄相关B细胞(ABCs)是一种独特的效应B细胞亚群，在老年雌性小鼠、感染模型和系统性自身免疫性疾病中数量增加。在小鼠中，ABCs被鉴定为CD11c+ CD11b+ CD21 - CD23 - T-bet+，在人类中，ABCs被鉴定为CD11c+ CD21 - CD27 - CXCR5 - FCRL5+ IgD - Tbet+。在自身免疫性环境中，这些B细胞富含自身抗体特异性，被认为是抗原经历的。此外，有证据表明，ABC可以在组织中持续存在，并在抗原再次暴露或先天刺激下迅速分化为抗体分泌细胞(ASCs)。转录因子(TFs) T-bet (T细胞中表达的T盒子)、IRF5(干扰素调节因子5)和IRF8在ABC中高表达，并被认为是ABC分化的功能调节剂。然而，除了免疫球蛋白G2a/c (IgG2a/c)同型转换外，T-bet对于ABC的积累和ABC特征的维持是不可或缺的。IRF5和IRF8在其他B细胞亚群中广泛表达，并被报道参与细胞活化、增殖、分化和功能。Zeb2调节ABC的特异性和细胞识别（Credit: Science ）为了确定ABC形成所必需的TF，作者筛选了这些细胞表达的所有TF，并鉴定出ZEB2(锌指E同源盒结合蛋白家族的成员)是小鼠和人类ABC规范和分化所需的关键调节因子。该研究强调了ABC吞噬凋亡细胞的先天能力，这一功能可能是TLR7激活和自身抗原向T细胞递呈的基础，同时也解释了它们的过度激活状态。JAK-STAT通路需要发挥Zeb2介导的ABC发育和致病性，通过JAK抑制剂提供了良好的治疗前景。以上结果表明ZEB2-JAK-STAT调控轴在ABC诱导分化过程中发挥着重要作用，通过干预ZEB2下游的靶通路JAK-STAT，可以有效缓解自身免疫疾病的发生和发展。原文链接https://www-science-org.libproxy1.nus.edu.sg/doi/10.1126/science.adf8531责编|探索君排版|探索君文章来源|“iNature”End往期精选围观Nat Med | 黄荷凤院士/张静澜/徐晨明团队发表综合性无创产前筛查临床研究成果热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Let-7家族miRNA或为癌症潜在免疫治疗靶点热文Nat Methods | 自主生物发光成像技术在真核生物中的创新进展

细胞疗法