TitleSchwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral sclerosis.
Publication TypeJournal Article
Year of Publication2020
AuthorsTrias E, Kovacs M, King PH, Si Y, Kwon Y, Varela V, Ibarburu S, Moura IC, Hermine O, Beckman JS, Barbeito L
Date Published2020 Jun

Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian-like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1 rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100β, GFAP, isolectin and/or p75 immunoreactivity. Different subsets of reactive SCs expressed colony-stimulating factor-1 (CSF1) and Interleukin-34 (IL-34) and closely interacted with numerous endoneurial CSF-1R-expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c-Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c-Kit in the sciatic nerves of SOD1 rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c-Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF-1R and c-Kit with masitinib in SOD1 rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies.

PubMed ID31859421
PubMed Central IDPMC7269115
Grant List#1104 / / Grupos I+D Program /
NINDS R01NS092651 / / Agencia Nacional de Investigación e Innovación /
R21 NS111275 / NS / NINDS NIH HHS / United States
R01 NS092651 / NS / NINDS NIH HHS / United States
P30 CA013148 / CA / NCI NIH HHS / United States
00482 / / Amyotrophic Lateral Sclerosis Association /
/ / Comisión Sectorial de Investigación Científica /
I01 BX004419 / BX / BLRD VA / United States
/ / Sistema Nacional de Investigadores /
I01 BX001148 / BX / BLRD VA / United States
/ / Universidad de la República /
COF 03/11 / / Institut Pasteur /
/ / Programa de Desarrollo de las Ciencias Básicas (PEDECIBA) /