Immune response in peripheral axons delays disease progression in SOD1G93A mice

Abstract

BackgroundIncreasing 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.MethodsFirst, 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.ResultsMuscle 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0732-2) contains supplementary material, which is available to authorized users.

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL‐34, and SCF in amyotrophic lateral sclerosis

“…SCs in ALS expressed significant levels of CSF1, IL‐34, and SCF and spatially interacted with immune effector cells bearing CSF‐1R and c‐Kit, suggesting a complex cellular interplay leading to local inflammation. Previous studies have shown infiltrating macrophages, mast cells and neutrophils (Chiu et al, ; Nardo et al, ; Trias et al, ) as well as SC proliferation (Deng et al, ) in the sciatic nerve of rodent ALS models. Here, we identified that these immune effectors express CSF‐1R and c‐Kit in human ALS nerves.…”

“…Previous studies on ALS postmortem peripheral nerve pathology have provided scarce information on SC phenotypes (Nardo et al, ; Riva et al, ). We examined SCs by immunohistochemical analysis of three nerve specimens from ALS subjects and three control donors, as well as one ALS ventral root specimen.…”

“…Mast cells are also recruited (Esposito, De Santis, Monteforte, & Baccari, ), orchestrating complex vascular and immune cell responses, including the chemoattraction of phagocytic neutrophils that further contribute to myelin clearance (Lindborg et al, ). In comparison, ALS nerve pathology similarly involves reactive changes in SCs (Keller, Gravel, & Kriz, ) as well as the recruitment of monocytes, macrophages, mast cells, and neutrophils (Chiu et al, ; Trias et al, ; Van Dyke et al, ).Such immune cell infiltration of the peripheral motor pathways in ALS has been linked to both protective and deleterious effects on motor neuron degeneration and disease progression (Nardo et al, ). However, the functional link between SCs and immune cell influx to degenerating peripheral nerves in ALS remains unknown.…”

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…In the CNS, ALS is typically accompanied by neuroinflammation involving the emergence of reactive microglia, astrocytes, and aberrant glial phenotypes (3)(4)(5). Evidence also shows activation of circulating immune cells (6), as well as immune cell infiltration of the ALS-degenerating peripheral nerves containing motor axons (7)(8)(9)(10).…”

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…These cells are known to permeate the BBB in specific regions and actively interact with the degenerative cellular microenvironment surrounding motor neurons and motor axons [81, 131, 133, 134]. It is also possible that chronic neuroinflammation restricted to the CNS can extend to skeletal muscles and then to other organs, becoming a systemic inflammation [135, 136].…”