Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice
Recent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomat...
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doaj-394d1a1af048412ab1b5250ff46087872021-04-06T11:06:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-11-011110.3389/fimmu.2020.575792575792Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A MiceDaniela Francesca Angelini0Federica De Angelis1Federica De Angelis2Valentina Vacca3Eleonora Piras4Chiara Parisi5Michele Nutini6Alida Spalloni7Francesca Pagano8Patrizia Longone9Luca Battistini10Flaminia Pavone11Sara Marinelli12Neuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyNeuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyCNR—National Research Council, Institute of Biochemistry and Cell Biology, Rome, ItalyCNR—National Research Council, Institute of Biochemistry and Cell Biology, Rome, ItalyNeuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyCNR—National Research Council, Institute of Biochemistry and Cell Biology, Rome, ItalyNeuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyNeuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyCNR—National Research Council, Institute of Biochemistry and Cell Biology, Rome, ItalyNeuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyNeuroimmunology Unit, IRCCS Santa Lucia Foundation, Rome, ItalyCNR—National Research Council, Institute of Biochemistry and Cell Biology, Rome, ItalyCNR—National Research Council, Institute of Biochemistry and Cell Biology, Rome, ItalyRecent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomatic) and 120 days (symptomatic) old SOD1-G93A mice, systemic, peripheral, and central innate and adaptive immune and inflammatory response, correlating it with the progression of the neurodegeneration in neuromuscular junction, sciatic nerves, and spinal cord. Surprisingly, we found a very initial (45–60 days) presence of IgG in sciatic nerves together with a gradual enhancement of A20/TNFAIP3 (protein controlling NF-κB signalling) and a concomitantly significant increase and activation of circulating mast cells (MCs) as well as MCs and macrophages in sciatic nerve and an enhancement of IL-6 and IL-10. This immunological frame coincided with a myelin aggregation. The 30–60 days old SOD1-G93A mice didn’t show real elements of neuroinflammation and neurodegeneration in spinal cord. In 120 days old mice macrophages and monocytes are widely diffused in sciatic nerves, peripheral neurodegeneration reaches the tip, high circulating levels of TNFα and IL-2 were found and spinal cord exhibits clear signs of neural damage and infiltrating immune cells. Our results underpin a clear immunological disorder at the origin of ALS axonopathy, in which MCs are involved in the initiation and sustaining of inflammatory events. These data cannot be considered a mere epiphenomenon of motor neuron degeneration and reveal new potential selective immune targets in ALS therapy.https://www.frontiersin.org/articles/10.3389/fimmu.2020.575792/fullperipheral nerve degenerationdemyelinationamyotrophic lateral sclerosismast cellspro-inflammatory cytokineautoimmunity |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniela Francesca Angelini Federica De Angelis Federica De Angelis Valentina Vacca Eleonora Piras Chiara Parisi Michele Nutini Alida Spalloni Francesca Pagano Patrizia Longone Luca Battistini Flaminia Pavone Sara Marinelli |
spellingShingle |
Daniela Francesca Angelini Federica De Angelis Federica De Angelis Valentina Vacca Eleonora Piras Chiara Parisi Michele Nutini Alida Spalloni Francesca Pagano Patrizia Longone Luca Battistini Flaminia Pavone Sara Marinelli Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice Frontiers in Immunology peripheral nerve degeneration demyelination amyotrophic lateral sclerosis mast cells pro-inflammatory cytokine autoimmunity |
author_facet |
Daniela Francesca Angelini Federica De Angelis Federica De Angelis Valentina Vacca Eleonora Piras Chiara Parisi Michele Nutini Alida Spalloni Francesca Pagano Patrizia Longone Luca Battistini Flaminia Pavone Sara Marinelli |
author_sort |
Daniela Francesca Angelini |
title |
Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice |
title_short |
Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice |
title_full |
Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice |
title_fullStr |
Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice |
title_full_unstemmed |
Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice |
title_sort |
very early involvement of innate immunity in peripheral nerve degeneration in sod1-g93a mice |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2020-11-01 |
description |
Recent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomatic) and 120 days (symptomatic) old SOD1-G93A mice, systemic, peripheral, and central innate and adaptive immune and inflammatory response, correlating it with the progression of the neurodegeneration in neuromuscular junction, sciatic nerves, and spinal cord. Surprisingly, we found a very initial (45–60 days) presence of IgG in sciatic nerves together with a gradual enhancement of A20/TNFAIP3 (protein controlling NF-κB signalling) and a concomitantly significant increase and activation of circulating mast cells (MCs) as well as MCs and macrophages in sciatic nerve and an enhancement of IL-6 and IL-10. This immunological frame coincided with a myelin aggregation. The 30–60 days old SOD1-G93A mice didn’t show real elements of neuroinflammation and neurodegeneration in spinal cord. In 120 days old mice macrophages and monocytes are widely diffused in sciatic nerves, peripheral neurodegeneration reaches the tip, high circulating levels of TNFα and IL-2 were found and spinal cord exhibits clear signs of neural damage and infiltrating immune cells. Our results underpin a clear immunological disorder at the origin of ALS axonopathy, in which MCs are involved in the initiation and sustaining of inflammatory events. These data cannot be considered a mere epiphenomenon of motor neuron degeneration and reveal new potential selective immune targets in ALS therapy. |
topic |
peripheral nerve degeneration demyelination amyotrophic lateral sclerosis mast cells pro-inflammatory cytokine autoimmunity |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2020.575792/full |
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