Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice
Open Access
- 20 November 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Immunology
Abstract
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-kappa B 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 TNF alpha 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.This publication has 79 references indexed in Scilit:
- Involvement of A20 in the molecular switch that activates the non-canonical NF-кB pathwayScientific Reports, 2013
- Inhibition of Fast Axonal Transport by Pathogenic SOD1 Involves Activation of p38 MAP KinasePLOS ONE, 2013
- The Analgesic Effect on Neuropathic Pain of Retrogradely Transported botulinum Neurotoxin A Involves Schwann Cells and AstrocytesPLOS ONE, 2012
- Mast cells and inflammationBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012
- Autoimmunity in Amyotrophic Lateral Sclerosis: Past and PresentNeurology Research International, 2011
- Wallerian degeneration: the innate-immune response to traumatic nerve injuryJournal of Neuroinflammation, 2011
- IL-17A is increased in the serum and in spinal cord CD8 and mast cells of ALS patientsJournal of Neuroinflammation, 2010
- Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3Human Molecular Genetics, 2008
- Neuron–glia crosstalk gets serious: role in pain hypersensitivityCurrent Opinion in Anaesthesiology, 2008
- Vesicular apparatus, including functional calcium channels, are present in developing rodent optic nerve axons and are required for normal node of Ranvier formationJournal Of Physiology-London, 2008