Immune response in peripheral axons delays disease progression in SOD1G93A mice

Giovanni Nardo, Maria Chiara Trolese, Giuseppe de Vito, Roberta Cecchi, Nilo Riva, Giorgia Dina, Paul R. Heath, Angelo Quattrini, Pamela J. Shaw, Vincenzo Piazza, Caterina Bendotti

Research output: Contribution to journalArticle

Abstract

Background: Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. Methods: First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Results: Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. Conclusions: These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course.

Original languageEnglish
Pages (from-to)261
JournalJournal of Neuroinflammation
Volume13
Issue number1
DOIs
Publication statusPublished - Oct 7 2016

Fingerprint

Axons
Disease Progression
Amyotrophic Lateral Sclerosis
Muscle Denervation
Schwann Cells
Peripheral Nervous System
Motor Neurons
Sciatic Nerve
Myelin Sheath
Immune System
Cell Proliferation
Intercellular Junctions
Raman Spectrum Analysis
Neuromuscular Junction
Denervation
Transgenes
Reverse Transcription
Macrophages
T-Lymphocytes
Polymerase Chain Reaction

Keywords

  • Amyotrophic lateral sclerosis
  • Immune system
  • Peripheral nervous system
  • SOD1 mice

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Immune response in peripheral axons delays disease progression in SOD1G93A mice. / Nardo, Giovanni; Trolese, Maria Chiara; de Vito, Giuseppe; Cecchi, Roberta; Riva, Nilo; Dina, Giorgia; Heath, Paul R.; Quattrini, Angelo; Shaw, Pamela J.; Piazza, Vincenzo; Bendotti, Caterina.

In: Journal of Neuroinflammation, Vol. 13, No. 1, 07.10.2016, p. 261.

Research output: Contribution to journalArticle

Nardo, Giovanni ; Trolese, Maria Chiara ; de Vito, Giuseppe ; Cecchi, Roberta ; Riva, Nilo ; Dina, Giorgia ; Heath, Paul R. ; Quattrini, Angelo ; Shaw, Pamela J. ; Piazza, Vincenzo ; Bendotti, Caterina. / Immune response in peripheral axons delays disease progression in SOD1G93A mice. In: Journal of Neuroinflammation. 2016 ; Vol. 13, No. 1. pp. 261.
@article{fbf0fd32b24a450cb498e3ec636ead2c,
title = "Immune response in peripheral axons delays disease progression in SOD1G93A mice",
abstract = "Background: Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. Methods: First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Results: Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. Conclusions: These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course.",
keywords = "Amyotrophic lateral sclerosis, Immune system, Peripheral nervous system, SOD1 mice",
author = "Giovanni Nardo and Trolese, {Maria Chiara} and {de Vito}, Giuseppe and Roberta Cecchi and Nilo Riva and Giorgia Dina and Heath, {Paul R.} and Angelo Quattrini and Shaw, {Pamela J.} and Vincenzo Piazza and Caterina Bendotti",
year = "2016",
month = "10",
day = "7",
doi = "10.1186/s12974-016-0732-2",
language = "English",
volume = "13",
pages = "261",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "NLM (Medline)",
number = "1",

}

TY - JOUR

T1 - Immune response in peripheral axons delays disease progression in SOD1G93A mice

AU - Nardo, Giovanni

AU - Trolese, Maria Chiara

AU - de Vito, Giuseppe

AU - Cecchi, Roberta

AU - Riva, Nilo

AU - Dina, Giorgia

AU - Heath, Paul R.

AU - Quattrini, Angelo

AU - Shaw, Pamela J.

AU - Piazza, Vincenzo

AU - Bendotti, Caterina

PY - 2016/10/7

Y1 - 2016/10/7

N2 - Background: Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. Methods: First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Results: Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. Conclusions: These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course.

AB - Background: Increasing evidence suggests that the immune system has a beneficial role in the progression of amyotrophic lateral sclerosis (ALS) although the mechanism remains unclear. Recently, we demonstrated that motor neurons (MNs) of C57SOD1G93A mice with slow disease progression activate molecules classically involved in the cross-talk with the immune system. This happens a lot less in 129SvSOD1G93A mice which, while expressing the same amount of transgene, had faster disease progression and earlier axonal damage. The present study investigated whether and how the immune response is involved in the preservation of motor axons in the mouse model of familial ALS with a more benign disease course. Methods: First, the extent of axonal damage, Schwann cell proliferation, and neuromuscular junction (NMJ) denervation were compared between the two ALS mouse models at the disease onset. Then, we compared the expression levels of different immune molecules, the morphology of myelin sheaths, and the presence of blood-derived immune cell infiltrates in the sciatic nerve of the two SOD1G93A mouse strains using immunohistochemical, immunoblot, quantitative reverse transcription PCR, and rotating-polarization Coherent Anti-Stokes Raman Scattering techniques. Results: Muscle denervation, axonal dysregulation, and myelin disruption together with reduced Schwann cell proliferation are prominent in 129SvSOD1G93A compared to C57SOD1G93A mice at the disease onset, and this correlates with a faster disease progression in the first strain. On the contrary, a striking increase of immune molecules such as CCL2, MHCI, and C3 was seen in sciatic nerves of slow progressor C57SOD1G93A mice and this was accompanied by heavy infiltration of CD8+ T lymphocytes and macrophages. These phenomena were not detectable in the peripheral nervous system of fast-progressing mice. Conclusions: These data show for the first time that damaged MNs in SOD1-related ALS actively recruit immune cells in the peripheral nervous system to delay muscle denervation and prolong the lifespan. On the contrary, the lack of this response has a negative impact on the disease course.

KW - Amyotrophic lateral sclerosis

KW - Immune system

KW - Peripheral nervous system

KW - SOD1 mice

UR - http://www.scopus.com/inward/record.url?scp=84990862372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84990862372&partnerID=8YFLogxK

U2 - 10.1186/s12974-016-0732-2

DO - 10.1186/s12974-016-0732-2

M3 - Article

AN - SCOPUS:84990862372

VL - 13

SP - 261

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

IS - 1

ER -