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病原体诱导的炎症反应通过调节未折叠蛋白反应而被氨基糖类似物 MON-DNJ 减弱。

Pathogen-induced inflammation is attenuated by the iminosugar MON-DNJ via modulation of the unfolded protein response.

机构信息

Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, UK.

Vanderbilt University School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

出版信息

Immunology. 2021 Nov;164(3):587-601. doi: 10.1111/imm.13393. Epub 2021 Aug 1.

Abstract

Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that cause injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad-spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signalling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide and fungal antigen-stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis-related inflammatory disorders associated with excess cytokine secretion.

摘要

脓毒症是一种危及生命的病症,涉及对感染因子的免疫反应失调,从而导致宿主组织和器官损伤。目前的治疗方法仅限于早期使用抗生素和支持性护理。虽然很有吸引力,但靶向抑制炎症级联反应中单个分子的策略并没有被证明是有益的。使用类固醇进行非靶向、全身性免疫抑制已显示出有限的疗效,并引起了对继发感染的关注。咪唑烷糖是一类小分子糖模拟物,根据立体化学,对糖处理酶具有独特的抑制谱。抑制宿主内质网驻留糖蛋白加工酶已被证明是一种广谱抗病毒策略,但对宿主糖蛋白产生的影响及其对信号级联的破坏的考虑有限。这项工作表明,咪唑烷糖可抑制人巨噬细胞中的登革热病毒、细菌脂多糖和真菌抗原刺激的细胞因子反应。尽管炎症介质的产生减少,但在存在咪唑烷糖的情况下,病毒复制受到抑制。转录组分析揭示了病原体诱导的内质网应激、由此产生的未折叠蛋白反应和炎症之间的关键相互作用。我们的工作表明,咪唑烷糖可以调节这些相互作用。基于这些发现,我们提出了咪唑烷糖作为治疗与细胞因子过度分泌相关的脓毒症相关炎症性疾病的新治疗作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/878d/8517592/b48f50bb4e29/IMM-164-587-g002.jpg

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