Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer's disease.

Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer's disease.
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小胶质细胞功能,INPP 5D/SHIP 1信号传导和NLRP 3炎性小体激活:对阿尔茨海默病的影响

DOI:
10.1186/s13024-023-00674-9
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发表时间:
2023-11-29
影响因子:
15.1
通讯作者:
Young-Pearse TL
Young-Pearse TL
中科院分区:
医学1区
文献类型:
--
作者:
Terzioglu G;Young-Pearse TL

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最近关于阿尔茨海默病(AD)的遗传学研究使小胶质细胞受到关注,因为与AD风险相关的基因位点在小胶质细胞中表达丰富。其中一些基因在小胶质细胞功能中起着重要作用。越来越多的证据表明,由ad相关基因INPP5D编码的SHIP1蛋白是小胶质细胞吞噬和免疫应答的重要调节因子。我们小组最近的一项研究发现,SHIP1在人ipsc来源的小胶质细胞(iMGs)中是NLRP3炎症小体的负调节因子。此外,我们还发现了SHIP1活性与AD大脑中炎性体激活之间存在联系的证据。NLRP3炎性小体是一种多蛋白复合物,可诱导促炎细胞因子的分泌,作为对抗病原体和内源性损伤信号的先天免疫反应的一部分。先前发表的研究表明,NLRP3炎症小体在AD中被激活,并参与AD相关病理。在这里,我们概述了目前对ad相关炎症背景下小胶质NLRP3炎性体的理解。然后,我们回顾了SHIP1已知的细胞内功能,包括它在磷酸肌苷信号传导中的作用,与小胶质吞噬受体(如TREM2)的相互作用,以及它与NLRP3炎症小体信号传导交叉的证据。通过对多个实验系统和死后分析中小胶质细胞信号通路之间复杂联系的严格检查,该领域将更好地为针对神经退行性疾病的小胶质细胞的新出现的治疗策略量身定制。
Recent genetic studies on Alzheimer’s disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial phagocytosis and immune response. A recent study from our group identified SHIP1 as a negative regulator of the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs). In addition, we found evidence for a connection between SHIP1 activity and inflammasome activation in the AD brain. The NLRP3 inflammasome is a multiprotein complex that induces the secretion of pro-inflammatory cytokines as part of innate immune responses against pathogens and endogenous damage signals. Previously published studies have suggested that the NLRP3 inflammasome is activated in AD and contributes to AD-related pathology. Here, we provide an overview of the current understanding of the microglial NLRP3 inflammasome in the context of AD-related inflammation. We then review the known intracellular functions of SHIP1, including its role in phosphoinositide signaling, interactions with microglial phagocytic receptors such as TREM2 and evidence for its intersection with NLRP3 inflammasome signaling. Through rigorous examination of the intricate connections between microglial signaling pathways across several experimental systems and postmortem analyses, the field will be better equipped to tailor newly emerging therapeutic strategies targeting microglia in neurodegenerative diseases.
DOI: 10.1038/s41588-022-01024-z
发表时间: 2022-04
期刊: NATURE GENETICS
影响因子: 30.8
作者:
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DOI: 10.1002/ijc.24748
发表时间: 2009-12-15
影响因子: 6.4
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通讯作者: Vogt, Peter K.
DOI: 10.1038/nn.2100
发表时间: 2008-05-01
影响因子: 25
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DOI: 10.1146/annurev-pathol-121808-102144
发表时间: 2010
期刊: Annual review of pathology
影响因子: --
作者:
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