Demyelinating diseases are often caused by a variety of triggers, including immune responses, viral infections, malnutrition, hypoxia, or genetic factors, all of which result in the loss of myelin in the nervous system. The accumulation of myelin debris at the lesion site leads to neuroinflammation and inhibits remyelination; therefore, it is crucial to promptly remove the myelin debris. Initially, Fc and complement receptors on cellular surfaces were the primary clearance receptors responsible for removing myelin debris. However, subsequent studies have unveiled the involvement of additional receptors, including Mac-2, TAM receptors, and the low-density lipoprotein receptor-related protein 1, in facilitating the removal process. In addition to microglia and macrophages, which serve as the primary effector cells in the disease phase, a variety of other cell types such as astrocytes, Schwann cells, and vascular endothelial cells have been demonstrated to engage in the phagocytosis of myelin debris. Furthermore, we have concluded that oligodendrocyte precursor cells, as myelination precursor cells, also exhibit this phagocytic capability. Moreover, our research group has innovatively identified the low-density lipoprotein receptor as a potential phagocytic receptor for myelin debris. In this article, we discuss the functional processes of various phagocytes in demyelinating diseases. We also highlight the alterations in signaling pathways triggered by phagocytosis, and provide a comprehensive overview of the various phagocytic receptors involved. Such insights are invaluable for pinpointing potential therapeutic strategies for the treatment of demyelinating diseases by targeting phagocytosis.
脱髓鞘疾病通常由多种诱因引起,包括免疫反应、病毒感染、营养不良、缺氧或遗传因素,所有这些因素都会导致神经系统髓鞘脱落。髓鞘碎片在病变部位堆积会导致神经发炎,抑制髓鞘再形成;因此,及时清除髓鞘碎片至关重要。最初,细胞表面的 Fc 和补体受体是负责清除髓鞘碎片的主要清除受体。然而,随后的研究发现,还有其他受体参与了清除过程,包括 Mac-2、TAM 受体和低密度脂蛋白受体相关蛋白 1。除了在疾病阶段作为主要效应细胞的小胶质细胞和巨噬细胞外,其他多种细胞类型,如星形胶质细胞、许旺细胞和血管内皮细胞也被证实参与了髓鞘碎片的吞噬。此外,我们还得出结论,少突胶质前体细胞作为髓鞘前体细胞,也具有这种吞噬能力。此外,我们的研究小组还创新性地发现低密度脂蛋白受体是一种潜在的髓鞘碎片吞噬受体。在本文中,我们将讨论脱髓鞘疾病中各种吞噬细胞的功能过程。我们还强调了由吞噬作用引发的信号通路的改变,并全面概述了所涉及的各种吞噬受体。这些见解对于通过靶向吞噬作用确定治疗脱髓鞘疾病的潜在治疗策略非常有价值。
{"title":"Myelin debris phagocytosis in demyelinating disease","authors":"Rui Gao, Sheng-Jiao Song, Meng-Yuan Tian, Li-Bin Wang, Yuan Zhang, Xing Li","doi":"10.1002/glia.24602","DOIUrl":"10.1002/glia.24602","url":null,"abstract":"<p>Demyelinating diseases are often caused by a variety of triggers, including immune responses, viral infections, malnutrition, hypoxia, or genetic factors, all of which result in the loss of myelin in the nervous system. The accumulation of myelin debris at the lesion site leads to neuroinflammation and inhibits remyelination; therefore, it is crucial to promptly remove the myelin debris. Initially, Fc and complement receptors on cellular surfaces were the primary clearance receptors responsible for removing myelin debris. However, subsequent studies have unveiled the involvement of additional receptors, including Mac-2, TAM receptors, and the low-density lipoprotein receptor-related protein 1, in facilitating the removal process. In addition to microglia and macrophages, which serve as the primary effector cells in the disease phase, a variety of other cell types such as astrocytes, Schwann cells, and vascular endothelial cells have been demonstrated to engage in the phagocytosis of myelin debris. Furthermore, we have concluded that oligodendrocyte precursor cells, as myelination precursor cells, also exhibit this phagocytic capability. Moreover, our research group has innovatively identified the low-density lipoprotein receptor as a potential phagocytic receptor for myelin debris. In this article, we discuss the functional processes of various phagocytes in demyelinating diseases. We also highlight the alterations in signaling pathways triggered by phagocytosis, and provide a comprehensive overview of the various phagocytic receptors involved. Such insights are invaluable for pinpointing potential therapeutic strategies for the treatment of demyelinating diseases by targeting phagocytosis.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 11","pages":"1934-1954"},"PeriodicalIF":5.4,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adina N. MacMahon Copas, Sarah F. McComish, Andreea Petrasca, Rachel McCormack, Daniel Ivers, Anna Stricker, Jean M. Fletcher, Maeve A. Caldwell
Astrocytes are mediators of homeostasis but contribute to neuroinflammation in Parkinson's disease (PD). Mounting evidence suggests involvement of peripheral immune cells in PD pathogenesis. Therefore, this study aimed to determine the potential role of peripheral immune secreted cytokines in modulating midbrain astrocyte reactivity. Human iPSC-derived midbrain astrocytes were exposed to 5% and 10% CD4+ T cell conditioned media (CD4CM) for 24 h, 72 h, and 7 days to assess chronic exposure. Additionally, astrocytes were exposed to the Th17 cell cytokine, IL-17A (10 ng/mL), alone and in combination with TNF-α (0.3 ng/mL) to assess potential synergistic effects of both cytokines at 24 h, 72 h, and 7 days. CD4CM induced acute and chronic alterations in midbrain astrocytes. Increased NFκB translocation to the nucleus, increased expression of the pro-inflammatory genes, IL-1β, CXCL10 at 24 h, C3, LCN2, IL-6 at 24 and 48 h, as well as an increase in their release of pro-inflammatory cytokines IL-6 and CXCL10 at both these time points were observed. A synergistic response to the combination of IL-17A and TNF-α on increasing inflammatory gene expression and cytokine release occurred. IL-17A and TNF-α increased intensity of S100β at 24 h, decreased nuclear area and increased circularity of astrocytes at 72 h. A synergistic effect on γH2AX intensity at 72 h and an increase in LDH release at 7 days was observed. Our results demonstrate that IL-17A and TNF-α act synergistically, enhancing midbrain astrocyte reactivity to a similar degree as CD4CM. This highlights the importance of the peripheral immune secreted cytokines in increasing the reactivity status of midbrain astrocytes, implicating their role in PD.
{"title":"CD4+ T cell-associated cytokines induce a chronic pro-inflammatory phenotype in induced pluripotent stem cell-derived midbrain astrocytes","authors":"Adina N. MacMahon Copas, Sarah F. McComish, Andreea Petrasca, Rachel McCormack, Daniel Ivers, Anna Stricker, Jean M. Fletcher, Maeve A. Caldwell","doi":"10.1002/glia.24601","DOIUrl":"10.1002/glia.24601","url":null,"abstract":"<p>Astrocytes are mediators of homeostasis but contribute to neuroinflammation in Parkinson's disease (PD). Mounting evidence suggests involvement of peripheral immune cells in PD pathogenesis. Therefore, this study aimed to determine the potential role of peripheral immune secreted cytokines in modulating midbrain astrocyte reactivity. Human iPSC-derived midbrain astrocytes were exposed to 5% and 10% CD4<sup>+</sup> T cell conditioned media (CD4CM) for 24 h, 72 h, and 7 days to assess chronic exposure. Additionally, astrocytes were exposed to the Th17 cell cytokine, IL-17A (10 ng/mL), alone and in combination with TNF-α (0.3 ng/mL) to assess potential synergistic effects of both cytokines at 24 h, 72 h, and 7 days. CD4CM induced acute and chronic alterations in midbrain astrocytes. Increased NFκB translocation to the nucleus, increased expression of the pro-inflammatory genes, IL-1β, CXCL10 at 24 h, C3, LCN2, IL-6 at 24 and 48 h, as well as an increase in their release of pro-inflammatory cytokines IL-6 and CXCL10 at both these time points were observed. A synergistic response to the combination of IL-17A and TNF-α on increasing inflammatory gene expression and cytokine release occurred. IL-17A and TNF-α increased intensity of S100β at 24 h, decreased nuclear area and increased circularity of astrocytes at 72 h. A synergistic effect on γH2AX intensity at 72 h and an increase in LDH release at 7 days was observed. Our results demonstrate that IL-17A and TNF-α act synergistically, enhancing midbrain astrocyte reactivity to a similar degree as CD4CM. This highlights the importance of the peripheral immune secreted cytokines in increasing the reactivity status of midbrain astrocytes, implicating their role in PD.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 11","pages":"2142-2154"},"PeriodicalIF":5.4,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cong Wang, Jing Dong, Heng Huang, Kegui Zhou, Zhenguo Liu, Richard Milner, Longxuan Li
Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to confer strong neuroprotective effects in acute ischemic stroke (AIS). However, as the vast majority of research findings to date are based on its functions in microglia, the precise role of TREM2 in astrocytes after AIS is unknown. Here, both loss- and gain-of-function experiments were employed to investigate how astrocytic TREM2 influences the pathogenesis of AIS in vivo and in vitro. Our results demonstrated that cerebral ischemia triggered induction of TREM2 expression on reactive astrocytes following AIS. In addition, astrocyte-specific TREM2 knockout mice exhibited much greater brain injury than TREM2 flox/flox controls following AIS, as evidenced by increased cerebral infarct volume, neuronal apoptosis and neurological deficit, which was associated with an increased expression of pro-inflammatory molecule complement component 3 (C3) on reactive astrocytes and activation of microglia/macrophages but decreased expression of S100 calcium binding protein A10 (S100A10) and arginase1 (Arg1) on reactive astrocytes. Mechanistic analyses revealed that astrocytic TREM2 alleviated brain injury by inhibiting detrimental actions of reactive astrocytes but promoting their neuro- and glioprotective actions via the kruppel-like transcription factor-4-nuclear factor-κB axis. Together, this study provides novel evidence for a critical protective role of astrocyte-derived TREM2 in AIS and highlights a potential therapeutic target for the treatment of AIS.
{"title":"Astrocyte-TREM2 alleviates brain injury by regulating reactive astrocyte states following ischemic stroke","authors":"Cong Wang, Jing Dong, Heng Huang, Kegui Zhou, Zhenguo Liu, Richard Milner, Longxuan Li","doi":"10.1002/glia.24597","DOIUrl":"10.1002/glia.24597","url":null,"abstract":"<p>Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to confer strong neuroprotective effects in acute ischemic stroke (AIS). However, as the vast majority of research findings to date are based on its functions in microglia, the precise role of TREM2 in astrocytes after AIS is unknown. Here, both loss- and gain-of-function experiments were employed to investigate how astrocytic TREM2 influences the pathogenesis of AIS in vivo and in vitro. Our results demonstrated that cerebral ischemia triggered induction of TREM2 expression on reactive astrocytes following AIS. In addition, astrocyte-specific TREM2 knockout mice exhibited much greater brain injury than TREM2 flox/flox controls following AIS, as evidenced by increased cerebral infarct volume, neuronal apoptosis and neurological deficit, which was associated with an increased expression of pro-inflammatory molecule complement component 3 (C3) on reactive astrocytes and activation of microglia/macrophages but decreased expression of S100 calcium binding protein A10 (S100A10) and arginase1 (Arg1) on reactive astrocytes. Mechanistic analyses revealed that astrocytic TREM2 alleviated brain injury by inhibiting detrimental actions of reactive astrocytes but promoting their neuro- and glioprotective actions via the kruppel-like transcription factor-4-nuclear factor-κB axis. Together, this study provides novel evidence for a critical protective role of astrocyte-derived TREM2 in AIS and highlights a potential therapeutic target for the treatment of AIS.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 11","pages":"2061-2078"},"PeriodicalIF":5.4,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rong Luo, Xiaojun Hu, Xin Li, Fan Lei, Ping Liao, Limei Yi, Xia Zhang, Bin Zhou, Ruotian Jiang
Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca2+ imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca2+ signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca2+ signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2PVH neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2PVH neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.
{"title":"Dysfunctional astrocyte glutamate uptake in the hypothalamic paraventricular nucleus contributes to visceral pain and anxiety-like behavior in mice with chronic pancreatitis","authors":"Rong Luo, Xiaojun Hu, Xin Li, Fan Lei, Ping Liao, Limei Yi, Xia Zhang, Bin Zhou, Ruotian Jiang","doi":"10.1002/glia.24595","DOIUrl":"10.1002/glia.24595","url":null,"abstract":"<p>Abdominal visceral pain is a predominant symptom in patients with chronic pancreatitis (CP); however, the underlying mechanism of pain in CP remains elusive. We hypothesized that astrocytes in the hypothalamic paraventricular nucleus (PVH) contribute to CP pain pathogenesis. A mouse model of CP was established by repeated intraperitoneal administration of caerulein to induce abdominal visceral pain. Abdominal mechanical stimulation, open field and elevated plus maze tests were performed to assess visceral pain and anxiety-like behavior. Fiber photometry, brain slice Ca<sup>2+</sup> imaging, electrophysiology, and immunohistochemistry were used to investigate the underlying mechanisms. Mice with CP displayed long-term abdominal mechanical allodynia and comorbid anxiety, which was accompanied by astrocyte glial fibrillary acidic protein reactivity, elevated Ca<sup>2+</sup> signaling, and astroglial glutamate transporter-1 (GLT-1) deficits in the PVH. Specifically, reducing astrocyte Ca<sup>2+</sup> signaling in the PVH via chemogenetics significantly rescued GLT-1 deficits and alleviated mechanical allodynia and anxiety in mice with CP. Furthermore, we found that GLT-1 deficits directly contributed to the hyperexcitability of VGLUT2<sup>PVH</sup> neurons in mice with CP, and that pharmacological activation of GLT-1 alleviated the hyperexcitability of VGLUT2<sup>PVH</sup> neurons, abdominal visceral pain, and anxiety in these mice. Taken together, our data suggest that dysfunctional astrocyte glutamate uptake in the PVH contributes to visceral pain and anxiety in mice with CP, highlighting GLT-1 as a potential therapeutic target for chronic pain in patients experiencing CP.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 11","pages":"2022-2037"},"PeriodicalIF":5.4,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Han Zhou, Rui-Kang Yang, Qian Li, Zhen Li, Yong-Chen Wang, Shu-Ying Li, Yanying Miao, Xing-Huai Sun, Zhongfeng Wang
Neuroinflammation plays important roles in retinal ganglion cell (RGC) degeneration in glaucoma. MicroRNA-146 (miR-146) has been shown to regulate inflammatory response in neurodegenerative diseases. In this study, whether and how miR-146 could affect RGC injury in chronic ocular hypertension (COH) experimental glaucoma were investigated. We showed that in the members of miR-146 family only miR-146a-5p expression was upregulated in COH retinas. The upregulation of miR-146a-5p was observed in the activated microglia and Müller cells both in primary cultured conditions and in COH retinas, but mainly occurred in microglia. Overexpression of miR-146a-5p in COH retinas reduced the levels pro-inflammatory cytokines and upregulated the levels of anti-inflammatory cytokines, which were further confirmed in the activated primary cultured microglia. Transfection of miR-146a-5p mimic increased the percentage of anti-inflammatory phenotype in the activated BV2 microglia, while transfection of miR-146a-5p inhibitor resulted in the opposite effects. Transfection of miR-146a-5p mimic/agomir inhibited the levels of interleukin-1 receptor associated kinase (IRAK1) and TNF receptor associated factor 6 (TRAF6) and phosphorylated NF-κB subunit p65. Dual luciferase reporter gene assay confirmed that miR-146a-5p could directly target IRAK1 and TRAF6. Moreover, downregulation of IRAK1 and TRAF6 by siRNA techniques or blocking NF-κB by SN50 in cultured microglia reversed the miR-146a-5p inhibitor-induced changes of inflammatory cytokines. In COH retinas, overexpression of miR-146a-5p reduced RGC apoptosis, increased RGC survival, and partially rescued the amplitudes of photopic negative response. Our results demonstrate that overexpression of miR-146a-5p attenuates RGC injury in glaucoma by reducing neuroinflammation through downregulating IRAK1/TRAF6/NF-κB signaling pathway in microglia.
{"title":"MicroRNA-146a-5p protects retinal ganglion cells through reducing neuroinflammation in experimental glaucoma","authors":"Han Zhou, Rui-Kang Yang, Qian Li, Zhen Li, Yong-Chen Wang, Shu-Ying Li, Yanying Miao, Xing-Huai Sun, Zhongfeng Wang","doi":"10.1002/glia.24600","DOIUrl":"10.1002/glia.24600","url":null,"abstract":"<p>Neuroinflammation plays important roles in retinal ganglion cell (RGC) degeneration in glaucoma. MicroRNA-146 (miR-146) has been shown to regulate inflammatory response in neurodegenerative diseases. In this study, whether and how miR-146 could affect RGC injury in chronic ocular hypertension (COH) experimental glaucoma were investigated. We showed that in the members of miR-146 family only miR-146a-5p expression was upregulated in COH retinas. The upregulation of miR-146a-5p was observed in the activated microglia and Müller cells both in primary cultured conditions and in COH retinas, but mainly occurred in microglia. Overexpression of miR-146a-5p in COH retinas reduced the levels pro-inflammatory cytokines and upregulated the levels of anti-inflammatory cytokines, which were further confirmed in the activated primary cultured microglia. Transfection of miR-146a-5p mimic increased the percentage of anti-inflammatory phenotype in the activated BV2 microglia, while transfection of miR-146a-5p inhibitor resulted in the opposite effects. Transfection of miR-146a-5p mimic/agomir inhibited the levels of interleukin-1 receptor associated kinase (IRAK1) and TNF receptor associated factor 6 (TRAF6) and phosphorylated NF-κB subunit p65. Dual luciferase reporter gene assay confirmed that miR-146a-5p could directly target IRAK1 and TRAF6. Moreover, downregulation of IRAK1 and TRAF6 by siRNA techniques or blocking NF-κB by SN50 in cultured microglia reversed the miR-146a-5p inhibitor-induced changes of inflammatory cytokines. In COH retinas, overexpression of miR-146a-5p reduced RGC apoptosis, increased RGC survival, and partially rescued the amplitudes of photopic negative response. Our results demonstrate that overexpression of miR-146a-5p attenuates RGC injury in glaucoma by reducing neuroinflammation through downregulating IRAK1/TRAF6/NF-κB signaling pathway in microglia.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 11","pages":"2115-2141"},"PeriodicalIF":5.4,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paul F. Cullen, William J. Gammerdinger, Shannan J. Ho Sui, Arpan Guha Mazumder, Daniel Sun
Cover Illustration: Confocal image of retinal astrocyte (green) isolated by microdissection from GFAP-Cre+ x Rpl22HA/HA mouse showing HA-tagged ribosomes (red) present throughout the cell, including within endfeet processes, indicating that ribosome associated mRNA throughout the cell can be isolated by immunoprecipitation. The image also indicates how well astrocyte morphology are preserved in our microdissection method. Nuclei are labeled with DAPI in blue. (See Cullen, P., et al, https://doi.org/10.1002/glia.24571)