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P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury
Purinergic 2 receptors (P2Rs) contribute to disease-related immune cell signaling and are upregulated in various pathological settings, including neuroinflammation. P2R inhibitors have been used to treat inflammatory diseases and can protect against complement-mediated cell injury. However, the mech...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606199/ https://www.ncbi.nlm.nih.gov/pubmed/35821382 http://dx.doi.org/10.1007/s13311-022-01269-w |
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author | Kalluri, Sudhakar Reddy Srivastava, Rajneesh Kenet, Selin Tanti, Goutam K. Dornmair, Klaus Bennett, Jeffrey L. Misgeld, Thomas Hemmer, Bernhard Wyss, Matthias T. Herwerth, Marina |
author_facet | Kalluri, Sudhakar Reddy Srivastava, Rajneesh Kenet, Selin Tanti, Goutam K. Dornmair, Klaus Bennett, Jeffrey L. Misgeld, Thomas Hemmer, Bernhard Wyss, Matthias T. Herwerth, Marina |
author_sort | Kalluri, Sudhakar Reddy |
collection | PubMed |
description | Purinergic 2 receptors (P2Rs) contribute to disease-related immune cell signaling and are upregulated in various pathological settings, including neuroinflammation. P2R inhibitors have been used to treat inflammatory diseases and can protect against complement-mediated cell injury. However, the mechanisms behind these anti-inflammatory properties of P2R inhibitors are not well understood, and their potential in CNS autoimmunity is underexplored. Here, we tested the effects of P2R inhibitors on glial toxicity in a mouse model of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a destructive CNS autoimmune disorder, in which autoantibodies against astrocytic surface antigen Aquaporin 4 (AQP4) mediate complement-dependent loss of astrocytes. Using two-photon microscopy in vivo, we found that various classes of P2R inhibitors prevented AQP4-IgG/complement-dependent astrocyte death. In vitro, these drugs inhibited the binding of AQP4-IgG or MOG-IgG to their antigen in a dose-dependent manner. Size-exclusion chromatography and circular dichroism spectroscopy revealed a partial unfolding of antibodies in the presence of various P2R inhibitors, suggesting a shared interference with IgG antibodies leading to their conformational change. Our study demonstrates that P2R inhibitors can disrupt complement activation by direct interaction with IgG. This mechanism is likely to influence the role of P2R inhibitors in autoimmune disease models and their therapeutic impact in human disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01269-w. |
format | Online Article Text |
id | pubmed-9606199 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-96061992022-11-29 P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury Kalluri, Sudhakar Reddy Srivastava, Rajneesh Kenet, Selin Tanti, Goutam K. Dornmair, Klaus Bennett, Jeffrey L. Misgeld, Thomas Hemmer, Bernhard Wyss, Matthias T. Herwerth, Marina Neurotherapeutics Original Article Purinergic 2 receptors (P2Rs) contribute to disease-related immune cell signaling and are upregulated in various pathological settings, including neuroinflammation. P2R inhibitors have been used to treat inflammatory diseases and can protect against complement-mediated cell injury. However, the mechanisms behind these anti-inflammatory properties of P2R inhibitors are not well understood, and their potential in CNS autoimmunity is underexplored. Here, we tested the effects of P2R inhibitors on glial toxicity in a mouse model of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a destructive CNS autoimmune disorder, in which autoantibodies against astrocytic surface antigen Aquaporin 4 (AQP4) mediate complement-dependent loss of astrocytes. Using two-photon microscopy in vivo, we found that various classes of P2R inhibitors prevented AQP4-IgG/complement-dependent astrocyte death. In vitro, these drugs inhibited the binding of AQP4-IgG or MOG-IgG to their antigen in a dose-dependent manner. Size-exclusion chromatography and circular dichroism spectroscopy revealed a partial unfolding of antibodies in the presence of various P2R inhibitors, suggesting a shared interference with IgG antibodies leading to their conformational change. Our study demonstrates that P2R inhibitors can disrupt complement activation by direct interaction with IgG. This mechanism is likely to influence the role of P2R inhibitors in autoimmune disease models and their therapeutic impact in human disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01269-w. Springer International Publishing 2022-07-12 2022-09 /pmc/articles/PMC9606199/ /pubmed/35821382 http://dx.doi.org/10.1007/s13311-022-01269-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Article Kalluri, Sudhakar Reddy Srivastava, Rajneesh Kenet, Selin Tanti, Goutam K. Dornmair, Klaus Bennett, Jeffrey L. Misgeld, Thomas Hemmer, Bernhard Wyss, Matthias T. Herwerth, Marina P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury |
title | P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury |
title_full | P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury |
title_fullStr | P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury |
title_full_unstemmed | P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury |
title_short | P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica: P2R Inhibitors Prevent Autoantibody Injury |
title_sort | p2r inhibitors prevent antibody-mediated complement activation in an animal model of neuromyelitis optica: p2r inhibitors prevent autoantibody injury |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606199/ https://www.ncbi.nlm.nih.gov/pubmed/35821382 http://dx.doi.org/10.1007/s13311-022-01269-w |
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