In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology

Marina Herwerth, Sudhakar Reddy Kalluri, Rajneesh Srivastava, Tatjana Kleele, Selin Kenet, Zsolt Illes, Doron Merkler, Jeffrey L Bennett, Thomas Misgeld, Bernhard Hemmer

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Abstract

OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and - importantly - axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.

METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice.

RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody concentration and complement, specifically C1q.

INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalAnnals of Neurology
Volume79
Issue number5
Pages (from-to)794-805
ISSN0364-5134
DOIs
Publication statusPublished - 2016

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Neuromyelitis Optica
Pathology
Wounds and Injuries
Complement C1q
Oligodendroglia
Demyelinating Diseases

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Herwerth, Marina ; Kalluri, Sudhakar Reddy ; Srivastava, Rajneesh ; Kleele, Tatjana ; Kenet, Selin ; Illes, Zsolt ; Merkler, Doron ; Bennett, Jeffrey L ; Misgeld, Thomas ; Hemmer, Bernhard. / In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology. In: Annals of Neurology. 2016 ; Vol. 79, No. 5. pp. 794-805.
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title = "In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology",
abstract = "OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and - importantly - axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice.RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody concentration and complement, specifically C1q.INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. This article is protected by copyright. All rights reserved.",
author = "Marina Herwerth and Kalluri, {Sudhakar Reddy} and Rajneesh Srivastava and Tatjana Kleele and Selin Kenet and Zsolt Illes and Doron Merkler and Bennett, {Jeffrey L} and Thomas Misgeld and Bernhard Hemmer",
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Herwerth, M, Kalluri, SR, Srivastava, R, Kleele, T, Kenet, S, Illes, Z, Merkler, D, Bennett, JL, Misgeld, T & Hemmer, B 2016, 'In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology', Annals of Neurology, vol. 79, no. 5, pp. 794-805. https://doi.org/10.1002/ana.24630

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology. / Herwerth, Marina; Kalluri, Sudhakar Reddy; Srivastava, Rajneesh; Kleele, Tatjana; Kenet, Selin; Illes, Zsolt; Merkler, Doron; Bennett, Jeffrey L; Misgeld, Thomas; Hemmer, Bernhard.

In: Annals of Neurology, Vol. 79, No. 5, 2016, p. 794-805.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica-related pathology

AU - Herwerth, Marina

AU - Kalluri, Sudhakar Reddy

AU - Srivastava, Rajneesh

AU - Kleele, Tatjana

AU - Kenet, Selin

AU - Illes, Zsolt

AU - Merkler, Doron

AU - Bennett, Jeffrey L

AU - Misgeld, Thomas

AU - Hemmer, Bernhard

N1 - © 2016 American Neurological Association.

PY - 2016

Y1 - 2016

N2 - OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and - importantly - axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice.RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody concentration and complement, specifically C1q.INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. This article is protected by copyright. All rights reserved.

AB - OBJECTIVE: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS, which resembles multiple sclerosis (MS). NMO differs from MS, however, in the distribution and histology of neuroinflammatory lesions and shows a more aggressive clinical course. Moreover, the majority of NMO patients carry IgG autoantibodies against aquaporin-4 (AQP4), an astrocytic water channel. Antibodies against AQP4 can damage astrocytes via complement, but NMO histopathology also shows demyelination, and - importantly - axon injury, which may determine permanent deficits following NMO relapses. The dynamics of astrocyte injury in NMO and the mechanisms by which toxicity spreads to axons are not understood.METHODS: Here, we establish in vivo imaging of the spinal cord, one of the main sites of NMO pathology, as a powerful tool to study the formation of experimental NMO-related lesions caused by human AQP4 antibodies in mice.RESULTS: We found that human AQP4 antibodies caused acute astrocyte depletion with initial oligodendrocyte survival. Within two hours of antibody application, we observed secondary axon injury in the form of progressive swellings. Astrocyte toxicity and axon damage were dependent on AQP4 antibody concentration and complement, specifically C1q.INTERPRETATION: In vivo imaging of the spinal cord reveals the swift development of NMO-related acute axon injury following AQP4 antibody-mediated astrocyte depletion. This approach will be useful in studying the mechanisms underlying the spread of NMO pathology beyond astrocytes, as well as in evaluating potential neuroprotective interventions. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ana.24630

DO - 10.1002/ana.24630

M3 - Journal article

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VL - 79

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EP - 805

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

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