免疫原性细胞死亡中的抑制性DAMPs及其临床意义。

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2021-03-22 DOI:10.15698/cst2021.04.247
Kazukuni Hayashi, Fotis Nikolos, Keith S Chan
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引用次数: 4

摘要

人们越来越认识到,死亡(或死亡)细胞对其所在组织产生重大的生物学影响——通过细胞死亡过程中表达或分泌的蛋白质和代谢物发挥旁分泌作用。例如,某些分子作为有效的有丝分裂原,促进邻近上皮细胞的再生。而其他被归类为损伤相关分子模式(DAMPs)的无数因素,其功能是“找到我”(引诱物)、“吃掉我”(吞噬)或“危险”(激活)信号,用于招募和激活效应免疫细胞(如树突状细胞),从而引发炎症。自从免疫原性细胞死亡(ICD)被发现以来,目前的观点认为DAMPs是先天免疫细胞动员和激活的免疫佐剂,最终导致CD8+ T细胞的抗肿瘤交叉启动。然而,目前尚不清楚这些免疫刺激DAMPs如何被抵消以避免免疫过度激活。我们最近的工作建立在这些基础之上,并引入了前列腺素E2 (PGE2)作为“抑制性”damp——ICD方程的一个新变量。前列腺素E2作为佐剂DAMPs的免疫抑制平衡;因此,从机制上排除了ICD。此外,长期争论的吉西他滨化疗的免疫原性被揭示是取决于抑制性DAMP阻断,而不是由于它不能促进DAMP表达(即钙网蛋白)。这些发现很有趣。首先,尽管存在吉西他滨诱导的标记DAMP,但抑制性DAMP(即PGE2)足以阻碍icd诱导的抗肿瘤免疫反应(图1a)。其次,与常规方法的免疫刺激DAMPs的药理学证实不同,抑制性DAMPs的缓解——将免疫刺激和抑制性DAMPs的平衡向免疫刺激DAMPs倾斜——足以使细胞死亡具有免疫原性,并将吉西他滨转化为icd诱导疗法(图1b)。在这篇微观综述中,我们推断了我们的发现,并暗示了抑制性DAMP(s)在药物发现、临床预后和治疗干预中的价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Inhibitory DAMPs in immunogenic cell death and its clinical implications.

Dying (or dead) cells are increasingly recognized to impose significant biological influence within their tissues of residence-exerting paracrine effects through proteins and metabolites that are expressed or secreted during cellular demise. For example, certain molecules function as potent mitogens, promoting the repopulation of neighboring epithelial cells. And other myriad of factors-classified as damage-associated molecular patterns (DAMPs)-function as "find me" (attractant), "eat me" (engulfment), or "danger" (activation) signals for recruiting and activating effector immune cells (e.g., dendritic cells) to initiate inflammation. Since the discovery of immunogenic cell death (ICD), the current dogma posits DAMPs as immunological adjuvants for innate immune cell mobilization and activation, which ultimately leads to the antitumoral cross-priming of CD8+ T cells. However, what is currently unknown is how these immunostimulatory DAMPs are counteracted to avoid immune-overactivation. Our recent work builds on these fundamentals and introduces prostaglandin E2 (PGE2) as an 'inhibitory' DAMP-a new variable to the ICD equation. Prostaglandin E2 functions as an immunosuppressive counterpoise of adjuvant DAMPs; and thus, mechanistically precludes ICD. Furthermore, the long-debated immunogenicity of gemcitabine chemotherapy was revealed to be contingent on inhibitory DAMP blockade and not due to its inability to promote DAMP expression (i.e., calreticulin) as previously reported. These findings were intriguing. First, despite the presence of gemcitabine-induced hallmark DAMPs, the inhibitory DAMP (i.e., PGE2) was sufficient to hinder the ICD-induced antitumoral immune response (Fig. 1a). And second, rather than pharmacologically substantiating immunostimulatory DAMPs as conventionally approached, the mitigation of the inhibitory DAMP-tipping the immunostimulatory and inhibitory DAMP balance in favor of immunostimulatory DAMPs-was sufficient to render the cell death immunogenic and converted gemcitabine into an ICD-inducing therapy (Fig. 1b). In this microreview, we extrapolate our findings and implicate the value of inhibitory DAMP(s) in drug discovery, its use for clinical prognosis, and as target(s) for therapeutic intervention.

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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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