Pacritinib Inhibition of IRAK1 Blocks Aberrant TLR8 Signalling by SARS-CoV-2 and HIV-1-Derived RNA.

IF 4.7 3区 医学 Q2 IMMUNOLOGY
Journal of Innate Immunity Pub Date : 2023-01-01 Epub Date: 2022-07-04 DOI:10.1159/000525292
Grant R Campbell, Pratima Rawat, Stephen A Spector
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引用次数: 5

Abstract

Macrophages promote an early host response to infection by releasing pro-inflammatory cytokines such as interleukin (IL) 1β (IL-1β), tumour necrosis factor (TNF), and IL-6. One of the mechanisms through which cells sense pathogenic microorganisms is through Toll-like receptors (TLRs). IL-1 receptor-associated kinase (IRAK) 1, IRAK2, IRAK3, and IRAK4 are integral to TLR and IL-1 receptor signalling pathways. Recent studies suggest a role for aberrant TLR8 and NLRP3 inflammasome activation during both COVID-19 and HIV-1 infection. Here, we show that pacritinib inhibits the TLR8-dependent pro-inflammatory cytokine response elicited by GU-rich single-stranded RNA derived from SARS-CoV-2 and HIV-1. Using genetic and pharmacologic inhibition, we demonstrate that pacritinib inhibits IRAK1 phosphorylation and ubiquitination which then inhibits the recruitment of the TAK1 complex to IRAK1, thus inhibiting the activation of downstream signalling and the production of pro-inflammatory cytokines.

Pacritinib抑制IRAK1阻断SARS-CoV-2和hiv -1衍生RNA的异常TLR8信号传导
巨噬细胞通过释放促炎细胞因子,如白细胞介素(IL) 1β (IL-1β)、肿瘤坏死因子(TNF)和IL-6,促进宿主对感染的早期反应。细胞感知病原微生物的机制之一是toll样受体(TLRs)。IL-1受体相关激酶(IRAK) 1、IRAK2、IRAK3和IRAK4是TLR和IL-1受体信号通路的组成部分。最近的研究表明,在COVID-19和HIV-1感染期间,TLR8和NLRP3炎症小体的异常激活都起着重要作用。在这里,我们发现pacritinib抑制来自SARS-CoV-2和HIV-1的富含gu的单链RNA引发的tlr8依赖性促炎细胞因子反应。通过遗传和药理学抑制,我们证明pacritinib抑制IRAK1的磷酸化和泛素化,从而抑制TAK1复合物向IRAK1的募集,从而抑制下游信号传导的激活和促炎细胞因子的产生。
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来源期刊
Journal of Innate Immunity
Journal of Innate Immunity 医学-免疫学
CiteScore
10.50
自引率
1.90%
发文量
35
审稿时长
7.5 months
期刊介绍: The ''Journal of Innate Immunity'' is a bimonthly journal covering all aspects within the area of innate immunity, including evolution of the immune system, molecular biology of cells involved in innate immunity, pattern recognition and signals of ‘danger’, microbial corruption, host response and inflammation, mucosal immunity, complement and coagulation, sepsis and septic shock, molecular genomics, and development of immunotherapies. The journal publishes original research articles, short communications, reviews, commentaries and letters to the editors. In addition to regular papers, some issues feature a special section with a thematic focus.
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