TLR4: the fall guy in sepsis?

IF 4.1 Q2 CELL BIOLOGY
Joseph Menassa, Christina Nedeva, Corey Pollock, Hamsa Puthalakath
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引用次数: 4

Abstract

Sepsis and its impact on human health can be traced back to 1000 BC and continues to be a major health burden today. It causes about 11 million deaths world-wide of which, more than a third are due to neonatal sepsis. There is no effective treatment other than fluid resuscitation therapy and antibiotic treatment that leave patients immunosuppressed and vulnerable to nosocomial infections. Added to that, ageing population and the emergence of antibiotic resistant bacteria pose new challenges. Most of the deleterious effects of sepsis are due to the host response to the systemic infection. In the initial phase of infection, hyper activation of the immune system leads to cytokine storm, which could lead to organ failure and this accounts for about 15% of overall deaths. However, the subsequent immune paralysis phase (mostly attributed to apoptotic death of immune cells) accounts for about 85% of all deaths. Past clinical trials (more than 100 in the last 30 years) all targeted the inflammatory phase with little success, predictably, for inflammation is a necessary process to fight infection. In order to identify the regulators of immune cell death during sepsis, we carried out an unbiased, whole genome CRISPR screening in mice and identified Trigger Receptor Expressed in Myeloid-like 4 (Treml4) as the receptor that controls both the inflammatory phase and the immune suppression phase in sepsis (Nedeva et al. (2020) Nature Immunol, doi: 10.1038/s41590-020-0789-z). Characterising the Treml4 gene knockout mice revealed new insights into the relative roles of TLR4 and TREML4 in inducing the inflammatory cytokine storm during sepsis.

TLR4:败血症的替罪羊?
败血症及其对人类健康的影响可追溯到公元前1000年,至今仍是一个主要的健康负担。它在全世界造成约1100万人死亡,其中三分之一以上是由于新生儿败血症。除了液体复苏疗法和抗生素治疗之外,没有其他有效的治疗方法,这使得患者免疫抑制,容易受到医院感染。此外,人口老龄化和抗生素耐药细菌的出现也构成了新的挑战。大多数败血症的有害影响是由于宿主对全身感染的反应。在感染的初始阶段,免疫系统的过度激活导致细胞因子风暴,这可能导致器官衰竭,这占总死亡人数的15%左右。然而,随后的免疫麻痹阶段(主要归因于免疫细胞凋亡)约占所有死亡的85%。过去的临床试验(在过去的30年里超过100次)都是针对炎症阶段的,但几乎没有成功,因为炎症是对抗感染的必要过程。为了确定脓毒症期间免疫细胞死亡的调节因子,我们在小鼠中进行了无偏的全基因组CRISPR筛选,并鉴定出髓样细胞4表达的触发受体(trem14)是脓毒症中控制炎症期和免疫抑制期的受体(Nedeva et al. (2020) Nature Immunol, doi: 10.1038/s41590-020-0789-z)。Treml4基因敲除小鼠的特征揭示了TLR4和Treml4在脓毒症期间诱导炎症细胞因子风暴中的相对作用。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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