Scale bar: 20 m. The spinal cord was removed and postfixed with 4% PFA (6 hours, 4C). Their combined citations are counted . (E) Immunofluorescence staining confirms AQP4 protein expression in the spinal cord of representative WT mouse (top right) and its absence in AQP4null mouse (bottom right). Clinical utility of testing AQP4-IgG in CSF: Guidance for physicians. Targeting of microglia and their bidirectional signals is an attractive therapeutic option because the pertinent molecules are predominantly expressed by activated microglia and not in basal conditions. The number of microglial process convergence events observed 12 hours after injecting NMO-IgG was significantly increased but fewer convergence events occurred after the same period of control-IgG infusion (Figure 7F). After washing, appropriate secondary antibody was applied (60 minutes at 22C; 1:500, Alexa Fluor 594, Life Technologies or Alexa Fluor 488, Life Technologies). Consistently, using caspase-3 staining, we also did not observe neuronal apoptosis in either control or NMO-IgGinfused mice (Supplemental Figure 2D). Long-Jun Wu, PhD - Associate Professor Google Scholar. The ensuing motor impairment recapitulated paralytic signs encountered in patients with early-attack-phase autoimmune AQP4 NMO spectrum disorders. These results are consistent with sublytic histopathological observations in NMO patients (19) and with neuropathology induced by CNS application of NMO-IgG in rodents, without complement (23, 25). 49: 2013: Genes . A single copy of these materials may be reprinted for noncommercial personal use only. Google Scholar A murine model of NMO using chronic infusion of NMO patientderived IgG. Yao X, Adams MS, Jones PD, Diederich CJ, Verkman AS. Microglial ablation prevents NMO-IgGinduced motor dysfunction. n = 5 mice (4 sections/mouse). Qin C, et al. TC, VAL, and LJW designed the research. Neuroimmune Interaction in Health and Disease: Madhuvika Murugan, PhD (Sep 2014 - Present), Harsh Bhavsar (2012 - 2013, Research Assistant), Peter Swiatkowski (2013 - 2014, Graduate Student), Daishi Tian (2014 - 2015, Visiting Scholar), Now at Huazhong University of Science and Technology, Junli Liu (2014 - 2015, Visiting Scholar), Now at Fourth Military Medical University, Aparna Mukherjee (2013 - 2015, Master student), Lijun Zhou, PhD (2014 - 2016, Visting Scholar). We showed further that an AQP4 extracellular domainspecific mouse monoclonal IgG (1 g/day) induced similar motor impairment in WT mice (Figure 1G), but not in AQP4null mice (Figure 1H). Overview; Fingerprint; Network; Grants (4) Research output (170) Similar Profiles (1) If you made any changes in Pure these will be visible here soon. NMO-IgG induces astrocyte-microglia interaction. Data presented as the mean SEM. 18, 2014: Dr. Long-Jun Wu was invited to give a talk at Comprehensive Epilepsy Center, New York University. The use of advanced genetic tools along with a combination of two-photon imaging, electrophysiology, electroencephalography, molecular biology techniques and awake-behavioral studies in rodent models help Dr. Wu and his colleagues identify microglia-specific targets to alleviate neuropathic pain, improve seizure and stroke outcomes, and treat autoimmune diseases like neuromyelitis optica. Latency to fall improved over the course of 2 weeks, but motor impairment remained at that point by comparison with control-IgG recipients (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI134816DS1). Thats all we know. Study approval. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Google Scholar: TC was supported by a postdoctoral fellowship from the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology. Hippocampal tissue slices (400 m thick) prepared from P14P21 mice were incubated in imaging media. The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model. Lucchinetti CF, Guo Y, Popescu BF, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Guo Y, et al. 2628). Email: longjunwu@ust.hk Scopus: 57724636100 Google Scholar: P3G4U4AAAAAJ ResearcherID: AAD-4694-2019 ORCID: 0000-0002-7580-5503 Co-authorship graph Publications Bibliometrics Rotarod performance was tested using a 5-lane apparatus (Med Associates Inc), starting at 4 rounds per minute, and uniformly accelerating over a 5-minute period to 40 rounds per minute. in: Scale bar: 20 m. It is remarkable that NMO-IgG did not induce significant motor impairment during the period of maximal microglial depletion (Figure 6C). The astrocytic glutamate transporter, EAAT2, cointernalizes with AQP4 after IgG cross-linking (10). Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. The primary pathogenic effector is an aquaporin 4 (AQP4) water channelspecific immunoglobulin G (IgG) (24). P3G4U4AAAAAJ Conflict of interest: VAL shares in royalties derived from Mayo . (D) In ex vivo time-lapse imaging of brain slice from naive Cx3cr1gfp/+ mouse, processes of microglia converge toward pipette tip (red) containing recombinant C3a, by comparison with pipette containing artificial CSF (aCSF). PubMed They have also lived in Rochester, NY and Bronx, NY. Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. A role for humoral mechanisms in the pathogenesis of Devics neuromyelitis optica. | Liu, Y. Immune Environment in Glioblastoma (Feb 2023), Korsmeyer Award 25th Anniversary Collection (Jan 2023), Next-Generation Sequencing in Medicine (Jun 2022), New Therapeutic Targets in Cardiovascular Diseases (Mar 2022), Microglia complement astrocytes in neuromyelitis optica, American Society for Clinical Investigation. We interpret loss of NeuN immunoreactivity, in the face of axonal integrity and lack of apoptotic signaling, to be evidence of neuronal stress (i.e., subcytolytic neuronal pathology; ref. Experimenters were blind to drug treatments. Two-way ANOVA with Tukeys multiple-comparisons test were used to determine significance between time curves of different groups. Current relapse-sparing treatment options for NMO include intravenous adrenocorticosteroids, immunosuppressants, and agents that reduce circulating immunoglobulin levels, neutralize complement, or block IL-6 or its receptor. Common terms and phrases. (4) Activated microglia upregulate C1q production and interact with astrocytes, and (5) upregulate C1q, which may boost complement cascades leading to neuronal damage. Marine Environmental Science, HUANG, Weidong Google Scholar Wu LJ, Vadakkan KI, Zhuo M. ATP-induced chemotaxis of microglial processes requires P2Y receptor-activated initiation of outward potassium currents. Signaling by the cleavage product of an early complement component is a critical mediator of astrocyte-microglia interaction and NMO lesion progression. Howe CL, Kaptzan T, Magaa SM, Ayers-Ringler JR, LaFrance-Corey RG, Lucchinetti CF. n = 3 mice. 2020;130(8):40254038.https://doi.org/10.1172/JCI134816. JCI AQP4 water channelspecific IgG targeting CNS astrocytes is recognized to be the primary pathogenic effector of NMO (24), but it is unclear what mechanisms link this autoantibodys binding to the astrocytic plasma membrane and neuronal dysfunction. Of note, previous studies have implicated complement alternative pathwayactivated C3-C3aR signaling in demyelination (33) and neurodegeneration (34). PubMed (Client IP address: 149.28.192.166) All animal procedures were performed in accordance with NIH guidelines and with the approval of the Institutional Animal Care and Use Committee at the Mayo Clinic. No significant motor impairment ensued in C3aR/ or C3/ mice (Figure 9B and Supplemental Figure 9B) despite AQP4 loss (Supplemental Figure 10). Behavioral testing. (B) Bar graphs compare, after 5 days of control-IgG or NMO-IgG infusion, intensity of Iba1+ staining: Iba+ cell numbers and Iba+ soma volumes. Scale bar: 200 m. Particularly, he and his team study the molecular mechanism underlying microglial sensing and regulation of neuronal activities. Research activity per year. The earliest discernible CNS lesions in these mice exhibited both AQP4 loss and astrocytic activation (namely, enhanced GFAP and C3 immunoreactivities), reproducing in part the pathological changes observed in subcytolytic lesions of NMO patients (19). Together, these results support the upregulation of complement component synthesis and secretion by astrocytes following the binding of NMO-IgG. ResearcherID: |. Copyright: 2020, American Society for Clinical Investigation. Eyo UB, Wu LJ. AAD-4694-2019 In cord tissue of control-IgG recipients, AQP4 colocalized with the vasculature marker CD31, consistent with AQP4 expression in astrocytic end-feet (Figure 2D). We are recruiting postdocs, graduate students and research scientists with neuroscience and/or immunology background. n = 5 mice (4 sections/mouse). In contrast, spinal cord C3 immunoreactivity in mice infused with control-IgG was mainly restricted to the lumen of blood vessels, despite PBS washout before tissue fixation (normal plasma concentration is ~8 g/L). The enhanced immunoreactivity of astrocytic cytoplasmic C3 that we demonstrated in mice infused intrathecally with AQP4-IgG is consistent with the upregulated C3 gene transcription reported in cultured rodent astrocytes exposed to NMO-IgG (9). Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Top 2 Results for Longjun Wu. dblp: Longjun Cai View bibliometrics on Google Scholar Citations: P3G4U4AAAAAJ View bibliometrics on ResearcherID: AAD-4694-2019. Microglia in spinal cord sections of NMO-IgGrecipient mice exhibited striking C3a receptor (C3aR) upregulation (Figure 8C). Ingram G, et al. We further showed that microglial activation was secondary to C3aR signaling. Please see Google's Terms of Service posted at https://policies.google.com/terms in: Neuroimmune Interaction in Health and Disease:LongJun Wu, Long-Jun Wu, PhD, Professor and Consultant, Departments of Neurology, Neuroscience and Immunology, Mayo Clinic, Phone: 507-422-5135; Email: wu.longjun@mayo.edu, version 3.3.6.2.8.3Page loaded in 0.044 seconds, (1) The molecular signalingof microglia-neuron communication, (2) Microglia in synaptic function and neuronal circuits, (3) Microglia in pain, epilepsy, stroke, and autoimmune neurology. Select this result to view Longjun Wu's phone number, address, and more. ORCID: ***P < 0.001 by 2-tailed Students t test (B and D). Roemer SF, et al. This "Cited by" count includes citations to the following articles in Scholar. Five days later an osmotic minipump delivery system, containing human or mouse IgG, was placed subcutaneously over the right shoulder. Additionally, the soma volume of astrocytes in cord tissue of NMO-IgG recipients was greater, and their processes were thicker than in astrocytes of control-IgG recipients. Until all complement components are available in sufficient quantity to effect cytolysis of opsonized astrocytes, extracellularly, released C3a would amplify mutually stimulatory astrocyte-microglia interactions.
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Scale bar: 20 m. The spinal cord was removed and postfixed with 4% PFA (6 hours, 4C). Their combined citations are counted . (E) Immunofluorescence staining confirms AQP4 protein expression in the spinal cord of representative WT mouse (top right) and its absence in AQP4null mouse (bottom right). Clinical utility of testing AQP4-IgG in CSF: Guidance for physicians. Targeting of microglia and their bidirectional signals is an attractive therapeutic option because the pertinent molecules are predominantly expressed by activated microglia and not in basal conditions. The number of microglial process convergence events observed 12 hours after injecting NMO-IgG was significantly increased but fewer convergence events occurred after the same period of control-IgG infusion (Figure 7F). After washing, appropriate secondary antibody was applied (60 minutes at 22C; 1:500, Alexa Fluor 594, Life Technologies or Alexa Fluor 488, Life Technologies). Consistently, using caspase-3 staining, we also did not observe neuronal apoptosis in either control or NMO-IgGinfused mice (Supplemental Figure 2D). Long-Jun Wu, PhD - Associate Professor Google Scholar. The ensuing motor impairment recapitulated paralytic signs encountered in patients with early-attack-phase autoimmune AQP4 NMO spectrum disorders. These results are consistent with sublytic histopathological observations in NMO patients (19) and with neuropathology induced by CNS application of NMO-IgG in rodents, without complement (23, 25). 49: 2013: Genes . A single copy of these materials may be reprinted for noncommercial personal use only. Google Scholar A murine model of NMO using chronic infusion of NMO patientderived IgG. Yao X, Adams MS, Jones PD, Diederich CJ, Verkman AS. Microglial ablation prevents NMO-IgGinduced motor dysfunction. n = 5 mice (4 sections/mouse). Qin C, et al. TC, VAL, and LJW designed the research. Neuroimmune Interaction in Health and Disease: Madhuvika Murugan, PhD (Sep 2014 - Present), Harsh Bhavsar (2012 - 2013, Research Assistant), Peter Swiatkowski (2013 - 2014, Graduate Student), Daishi Tian (2014 - 2015, Visiting Scholar), Now at Huazhong University of Science and Technology, Junli Liu (2014 - 2015, Visiting Scholar), Now at Fourth Military Medical University, Aparna Mukherjee (2013 - 2015, Master student), Lijun Zhou, PhD (2014 - 2016, Visting Scholar). We showed further that an AQP4 extracellular domainspecific mouse monoclonal IgG (1 g/day) induced similar motor impairment in WT mice (Figure 1G), but not in AQP4null mice (Figure 1H). Overview; Fingerprint; Network; Grants (4) Research output (170) Similar Profiles (1) If you made any changes in Pure these will be visible here soon. NMO-IgG induces astrocyte-microglia interaction. Data presented as the mean SEM. 18, 2014: Dr. Long-Jun Wu was invited to give a talk at Comprehensive Epilepsy Center, New York University. The use of advanced genetic tools along with a combination of two-photon imaging, electrophysiology, electroencephalography, molecular biology techniques and awake-behavioral studies in rodent models help Dr. Wu and his colleagues identify microglia-specific targets to alleviate neuropathic pain, improve seizure and stroke outcomes, and treat autoimmune diseases like neuromyelitis optica. Latency to fall improved over the course of 2 weeks, but motor impairment remained at that point by comparison with control-IgG recipients (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI134816DS1). Thats all we know. Study approval. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Google Scholar: TC was supported by a postdoctoral fellowship from the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology. Hippocampal tissue slices (400 m thick) prepared from P14P21 mice were incubated in imaging media. The intrinsic pathogenic role of autoantibodies to aquaporin 4 mediating spinal cord disease in a rat passive-transfer model. Lucchinetti CF, Guo Y, Popescu BF, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Guo Y, et al. 2628). Email: longjunwu@ust.hk Scopus: 57724636100 Google Scholar: P3G4U4AAAAAJ ResearcherID: AAD-4694-2019 ORCID: 0000-0002-7580-5503 Co-authorship graph Publications Bibliometrics
Rotarod performance was tested using a 5-lane apparatus (Med Associates Inc), starting at 4 rounds per minute, and uniformly accelerating over a 5-minute period to 40 rounds per minute. in: Scale bar: 20 m.
It is remarkable that NMO-IgG did not induce significant motor impairment during the period of maximal microglial depletion (Figure 6C). The astrocytic glutamate transporter, EAAT2, cointernalizes with AQP4 after IgG cross-linking (10). Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. The primary pathogenic effector is an aquaporin 4 (AQP4) water channelspecific immunoglobulin G (IgG) (24). P3G4U4AAAAAJ Conflict of interest: VAL shares in royalties derived from Mayo . (D) In ex vivo time-lapse imaging of brain slice from naive Cx3cr1gfp/+ mouse, processes of microglia converge toward pipette tip (red) containing recombinant C3a, by comparison with pipette containing artificial CSF (aCSF). PubMed They have also lived in Rochester, NY and Bronx, NY. Neuromyelitis optica (NMO) is a severe inflammatory autoimmune CNS disorder triggered by binding of an IgG autoantibody to the aquaporin 4 (AQP4) water channel on astrocytes. A role for humoral mechanisms in the pathogenesis of Devics neuromyelitis optica. | Liu, Y. Immune Environment in Glioblastoma (Feb 2023), Korsmeyer Award 25th Anniversary Collection (Jan 2023), Next-Generation Sequencing in Medicine (Jun 2022), New Therapeutic Targets in Cardiovascular Diseases (Mar 2022), Microglia complement astrocytes in neuromyelitis optica, American Society for Clinical Investigation. We interpret loss of NeuN immunoreactivity, in the face of axonal integrity and lack of apoptotic signaling, to be evidence of neuronal stress (i.e., subcytolytic neuronal pathology; ref. Experimenters were blind to drug treatments. Two-way ANOVA with Tukeys multiple-comparisons test were used to determine significance between time curves of different groups. Current relapse-sparing treatment options for NMO include intravenous adrenocorticosteroids, immunosuppressants, and agents that reduce circulating immunoglobulin levels, neutralize complement, or block IL-6 or its receptor. Common terms and phrases. (4) Activated microglia upregulate C1q production and interact with astrocytes, and (5) upregulate C1q, which may boost complement cascades leading to neuronal damage. Marine Environmental Science, HUANG, Weidong
Google Scholar Wu LJ, Vadakkan KI, Zhuo M. ATP-induced chemotaxis of microglial processes requires P2Y receptor-activated initiation of outward potassium currents. Signaling by the cleavage product of an early complement component is a critical mediator of astrocyte-microglia interaction and NMO lesion progression. Howe CL, Kaptzan T, Magaa SM, Ayers-Ringler JR, LaFrance-Corey RG, Lucchinetti CF. n = 3 mice. 2020;130(8):40254038.https://doi.org/10.1172/JCI134816. JCI AQP4 water channelspecific IgG targeting CNS astrocytes is recognized to be the primary pathogenic effector of NMO (24), but it is unclear what mechanisms link this autoantibodys binding to the astrocytic plasma membrane and neuronal dysfunction. Of note, previous studies have implicated complement alternative pathwayactivated C3-C3aR signaling in demyelination (33) and neurodegeneration (34). PubMed (Client IP address: 149.28.192.166) All animal procedures were performed in accordance with NIH guidelines and with the approval of the Institutional Animal Care and Use Committee at the Mayo Clinic. No significant motor impairment ensued in C3aR/ or C3/ mice (Figure 9B and Supplemental Figure 9B) despite AQP4 loss (Supplemental Figure 10). Behavioral testing. (B) Bar graphs compare, after 5 days of control-IgG or NMO-IgG infusion, intensity of Iba1+ staining: Iba+ cell numbers and Iba+ soma volumes. Scale bar: 200 m.
Particularly, he and his team study the molecular mechanism underlying microglial sensing and regulation of neuronal activities. Research activity per year. The earliest discernible CNS lesions in these mice exhibited both AQP4 loss and astrocytic activation (namely, enhanced GFAP and C3 immunoreactivities), reproducing in part the pathological changes observed in subcytolytic lesions of NMO patients (19). Together, these results support the upregulation of complement component synthesis and secretion by astrocytes following the binding of NMO-IgG. ResearcherID: |. Copyright: 2020, American Society for Clinical Investigation. Eyo UB, Wu LJ. AAD-4694-2019 In cord tissue of control-IgG recipients, AQP4 colocalized with the vasculature marker CD31, consistent with AQP4 expression in astrocytic end-feet (Figure 2D). We are recruiting postdocs, graduate students and research scientists with neuroscience and/or immunology background. n = 5 mice (4 sections/mouse). In contrast, spinal cord C3 immunoreactivity in mice infused with control-IgG was mainly restricted to the lumen of blood vessels, despite PBS washout before tissue fixation (normal plasma concentration is ~8 g/L). The enhanced immunoreactivity of astrocytic cytoplasmic C3 that we demonstrated in mice infused intrathecally with AQP4-IgG is consistent with the upregulated C3 gene transcription reported in cultured rodent astrocytes exposed to NMO-IgG (9). Zekeridou A, Lennon VA. Aquaporin-4 autoimmunity. Top 2 Results for Longjun Wu. dblp: Longjun Cai View bibliometrics on Google Scholar Citations: P3G4U4AAAAAJ View bibliometrics on ResearcherID: AAD-4694-2019. Microglia in spinal cord sections of NMO-IgGrecipient mice exhibited striking C3a receptor (C3aR) upregulation (Figure 8C). Ingram G, et al. We further showed that microglial activation was secondary to C3aR signaling. Please see Google's Terms of Service posted at https://policies.google.com/terms in: Neuroimmune Interaction in Health and Disease:LongJun Wu, Long-Jun Wu, PhD, Professor and Consultant, Departments of Neurology, Neuroscience and Immunology, Mayo Clinic, Phone: 507-422-5135; Email: wu.longjun@mayo.edu, version 3.3.6.2.8.3Page loaded in 0.044 seconds, (1) The molecular signalingof microglia-neuron communication, (2) Microglia in synaptic function and neuronal circuits, (3) Microglia in pain, epilepsy, stroke, and autoimmune neurology. Select this result to view Longjun Wu's phone number, address, and more. ORCID: ***P < 0.001 by 2-tailed Students t test (B and D). Roemer SF, et al. This "Cited by" count includes citations to the following articles in Scholar. Five days later an osmotic minipump delivery system, containing human or mouse IgG, was placed subcutaneously over the right shoulder. Additionally, the soma volume of astrocytes in cord tissue of NMO-IgG recipients was greater, and their processes were thicker than in astrocytes of control-IgG recipients. Until all complement components are available in sufficient quantity to effect cytolysis of opsonized astrocytes, extracellularly, released C3a would amplify mutually stimulatory astrocyte-microglia interactions. Holiday Homes For Sale In Switzerland,
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