nach oben

Erschienen in:

19.10.2020 | Rapid Communications

CD137 Ligand-CD137 Interaction is Required For Inflammasome-Associated Brain Injury Following Ischemic Stroke

verfasst von: David Y. Fann, Emily Pauline Nickles, Luting Poh, Vismitha Rajeev, Sharmelee Selvaraji, Herbert Schwarz, Thiruma V. Arumugam

Erschienen in: NeuroMolecular Medicine | Ausgabe 4/2020

Einloggen, um Zugang zu erhalten

Abstract

The CD137L-CD137 axis is a potent co-stimulatory immune checkpoint regulator that forms a bidirectional signaling pathway between the CD137 ligand (CD137L) and CD137 receptor to regulate immunological activities. This study investigated the potential involvement of the CD137L-CD137 axis on inflammasome-associated brain injury and neurological deficits in a mouse model of focal ischemic stroke. Cerebral ischemia was induced in male C57BL/6J wild-type (WT), CD137L-deficient (CD137L KO) and CD137-deficient (CD137 KO) mice by middle cerebral artery occlusion (MCAO; 60 min), followed by reperfusion (6 h and 24 h). Brain infarct volume and neurological deficit scores were significantly lower in both CD137L KO and CD137 KO mice compared to WT controls. Moreover, CD137L-deficient brains had significantly lower levels of the pyroptotic protein, NT-Gasdermin D, while CD137-deficient brains had significantly lower levels of the pro-apoptotic proteins, cleaved caspase-3, pyroptotic protein, NT-Gasdermin D, and of the secondary pyroptotic protein NT-Gasdermin E, following ischemic stroke. This protection by CD137L and CD137 deletion was associated with a significant decrease in inflammasome signaling. In conclusion, our data provide evidence for the first time that the CD137L-CD137 axis contributes to brain injury and neurological deficits by activating the inflammasome signaling pathway following ischemic stroke.

Nur mit Berechtigung zugänglich

Dharmadhikari, B., Nickles, E., Harfuddin, Z., et al. (2018). CD137L dendritic cells induce potent response against cancer-associated viruses and polarize human CD8+ T cells to Tc1 phenotype. Cancer Immunology, Immunotherapy, 67(6), 893–905.PubMed

Etxeberria, I., Glez-Vaz, J., Teijeira, Á., & Melero, I. (2020). New emerging targets in cancer immunotherapy: CD137/4-1BB costimulatory axis. ESMO Open., 4(Suppl 3), e000733.PubMedPubMedCentral

Fann, D. Y., Lee, S. Y., Manzanero, S., Chunduri, P., Sobey, C. G., & Arumugam, T. V. (2013). Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev., 12(4), 941–966.PubMed

Fann, D. Y., Lee, S. Y., Manzanero, S., et al. (2013). Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis., 4(9), e790.PubMed

Fann, D. Y., Lim, Y. A., Cheng, Y. L., et al. (2018). Evidence that NF-κB and MAPK signaling promotes NLRP INFLAMMASOME ACTIVATION IN NEURONS FOLLOWING ISCHEMIC STROKe. Molecular Neurobiology, 55(2), 1082–1096.PubMed

Frederick Lo, C., Ning, X., Gonzales, C., & Ozenberger, B. A. (2008). Induced expression of death domain genes NALP1 and NALP5 following neuronal injury. Biochemical and Biophysical Research Communications, 366(3), 664–669.PubMed

He, Q., You, H., Li, X. M., Liu, T. H., Wang, P., & Wang, B. E. (2012). HMGB1 promotes the synthesis of pro-IL-1β and pro-IL-18 by activation of p38 MAPK and NF-κB through receptors for advanced glycation end-products in macrophages. Asian Pacific Journal of Cancer Prevention, 13(4), 1365–1370.PubMed

He, Y., Ao, D. H., Li, X. Q., et al. (2018). Increased soluble CD137 Levels and CD4+ T-Cell-associated expression of CD137 in Acute atherothrombotic stroke. Clinical and Translational science, 11(4), 428–434.PubMedPubMedCentral

Jang, I. K., Lee, Z. H., Kim, Y. J., Kim, S. H., & Kwon, B. S. (1998). Human 4–1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochemical and Biophysical Research Communications, 242(3), 613–620.PubMed

Kang, S. J., Wang, S., Hara, H., et al. (2000). Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. Journal of Cell Biology, 149(3), 613–622.PubMedPubMedCentral

Kayagaki, N., Stowe, I. B., Lee, B. L., et al. (2015). Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature, 526(7575), 666–671.PubMed

Li, X. Q., Wang, Y. Y., Yang, T. T., et al. (2019). Increased peripheral CD137 expression in a mouse model of permanent focal cerebral ischemia. Cellular and Molecular Neurobiology, 39(3), 451–460.PubMed

Luu, K., Shao, Z., & Schwarz, H. (2020). The relevance of soluble CD137 in the regulation of immune responses and for immunotherapeutic intervention. Journal of Leukocyte Biology, 107(5), 731–738.PubMed

Mak, A., & Schwarz, H. (2019). The progress of investigating the CD137-CD137L axis as a potential target for systemic lupus erythematosus. Cells, 8(9), 1044.PubMedCentral

Mak, A., Dharmadhikari, B., Kow, N. Y., et al. (2019). Deletion of CD137 ligand exacerbates renal and cutaneous but alleviates cerebral manifestations in lupus. Front Immunology, 10, 1411.

Martínez Gómez, J. M., Croxford, J. L., Yeo, K. P., Angeli, V., Schwarz, H., & Gasser, S. (2012). Development of experimental autoimmune encephalomyelitis critically depends on CD137 ligand signaling. Journal of Neuroscience, 32(50), 18246–18252.PubMed

Orning, P., Weng, D., Starheim, K., et al. (2018). Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science, 362(6418), 1064–1069.PubMedPubMedCentral

Poh, L., Kang, S. W., Baik, S. H., et al. (2019). Evidence that NLRC4 inflammasome mediates apoptotic and pyroptotic microglial death following ischemic stroke. Brain, Behavior, and Immunity, 75, 34–47.PubMed

Rogers, C., Erkes, D. A., Nardone, A., Aplin, A. E., Fernandes-Alnemri, T., & Alnemri, E. S. (2019). Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nature Communications, 10(1), 1689.PubMedPubMedCentral

Rogers, C., Fernandes-Alnemri, T., Mayes, L., Alnemri, D., Cingolani, G., & Alnemri, E. S. (2017). Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nature Communications, 8, 14128.PubMedPubMedCentral

Sagulenko, V., Vitak, N., Vajjhala, P. R., Vince, J. E., & Stacey, K. J. (2018). Caspase-1 Is an apical caspase leading to caspase-3 cleavage in the AIM2 inflammasome response, independent of caspase-8. Journal of Molecular Biology, 430(2), 238–247.PubMed

Shi, J., Zhao, Y., Wang, K., et al. (2015). Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 526(7575), 660–665.PubMed

Söderström, L. Å., Tarnawski, L., & Olofsson, P. S. (2018). CD137: a checkpoint regulator involved in atherosclerosis. Atherosclerosis., 272, 66–72.PubMed

Söllner, L., Shaqireen, D. O., Kwajah, M. M., Wu, J. T., & Schwarz, H. (2007). Signal transduction mechanisms of CD137 ligand in human monocytes. Cell Signal, 19(9), 1899–1908.PubMed

Wong, H. Y., & Schwarz, H. (2020). CD137 / CD137 ligand signalling regulates the immune balance: a potential target for novel immunotherapy of autoimmune diseases. Journal of Autoimmunity, 112, 102499.PubMed

Yeo, Y. A., Martínez Gómez, J. M., Croxford, J. L., Gasser, S., Ling, E. A., & Schwarz, H. (2012). CD137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen species. J Neuroinflammation., 9, 173.PubMedPubMedCentral

Yun, C. H., Lee, H. M., Lee, S. C., Kim, B. S., Park, J. W., & Lee, B. J. (2013). Involvement of CD137 ligand signaling in neural stem cell death. Molecules and Cells, 36(3), 245–251.PubMedPubMedCentral

Zeng, Q., Mallilankaraman, K., & Schwarz, H. (2019). Increased Akt-driven glycolysis Is the basis for the higher potency of CD137L-DCs. Front Immunology, 10, 868.

Zeng, Q., Soe, Y. M., Lim, Y., Sobota, R. M., & Schwarz, H. (2020). CD137 ligand interacts with CD32a to trigger reverse CD137 ligand signaling. Cellular & Molecular Immunology. https://doi.org/10.1038/s41423-020-0370-6CrossRefPubMed

Zhang, D., Qian, J., Zhang, P., et al. (2019). Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro. Journal of Neuroscience Research, 97(6), 645–660.PubMed

Zhang, J., Chen, G., Zhou, D., & Wang, Z. (2011). Expression of CD137 in the cerebral artery after experimental subarachnoid hemorrhage in rats: a pilot study. Brain Research, 1386, 200–208.PubMed

Zhang, S., Li, Z., Zhang, R., et al. (2017). Novel CD137 Gene polymorphisms and susceptibility to Ischemic stroke in the Northern Chinese Han population. Neuromolecular Medicine, 19(2–3), 413–422.PubMed

Zheng, D., Liwinski, T., & Elinav, E. (2020). Inflammasome activation and regulation: toward a better understanding of complex mechanisms. Cell Discovery, 6, 36.PubMedPubMedCentral

Titel: CD137 Ligand-CD137 Interaction is Required For Inflammasome-Associated Brain Injury Following Ischemic Stroke
verfasst von: David Y. Fann
Emily Pauline Nickles
Luting Poh
Vismitha Rajeev
Sharmelee Selvaraji
Herbert Schwarz
Thiruma V. Arumugam
Publikationsdatum: 19.10.2020
Verlag: Springer US
Erschienen in: NeuroMolecular Medicine / Ausgabe 4/2020
Print ISSN: 1535-1084
Elektronische ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-020-08623-1

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Sind Frauen die fähigeren Ärzte?

30.04.2024 Gendermedizin Nachrichten

Patienten, die von Ärztinnen behandelt werden, dürfen offenbar auf bessere Therapieergebnisse hoffen als Patienten von Ärzten. Besonders gilt das offenbar für weibliche Kranke, wie eine Studie zeigt.

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Frühe Alzheimertherapie lohnt sich

25.04.2024 AAN-Jahrestagung 2024 Nachrichten

Ist die Tau-Last noch gering, scheint der Vorteil von Lecanemab besonders groß zu sein. Und beginnen Erkrankte verzögert mit der Behandlung, erreichen sie nicht mehr die kognitive Leistung wie bei einem früheren Start. Darauf deuten neue Analysen der Phase-3-Studie Clarity AD.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2020

Oxytocin Reduces Brain Injury and Maintains Blood–Brain Barrier Integrity After Ischemic Stroke in Mice

HLA in Alzheimer’s Disease: Genetic Association and Possible Pathogenic Roles

A Review of Functional Electrical Stimulation Treatment in Spinal Cord Injury

Transcriptomic Heterogeneity of Alzheimer’s Disease Associated with Lipid Genetic Risk

miR-146a Mimics Ameliorates Traumatic Brain Injury Involving JNK and NF-κB Signaling Pathway

Cell-Free Extracellular Vesicles Derived from Human Bone Marrow Endothelial Progenitor Cells as Potential Therapeutics for Microvascular Endothelium Restoration in ALS