CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves.

Anna Martínez-Muriana,Xavier Navarro,Ruben López-Vales,Rosario Osta,Adrian Olmos-Alonso,V Hugh Perry,Isaac Francos-Quijorna,Renzo Mancuso,Diego Gomez-Nicola

doi:10.1038/srep25663

Abstract

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1G93A transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1G93A mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1G93A mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease.

Highlights

Lymphocytes subsets contribute to slowing disease progression[13], whereas the function of macrophages, which invade the peripheral nerves during disease progression[14,15], is yet to be defined
This data correlated with the measurement of the protein levels of CSF1 at the lumbar spinal cord of SOD1G93A mice, with upregulated levels at 16 weeks when compared to WT littermates (Fig. 1i)
These findings show that the activation of Colony-stimulating factor 1 receptor (CSF1R) signalling via CSF1 occurs in the spinal cord of SOD1G93A mice at late stages of the disease

Summary

Introduction

Lymphocytes subsets contribute to slowing disease progression[13], whereas the function of macrophages, which invade the peripheral nerves during disease progression[14,15], is yet to be defined. A previous study showed that systemic administration of CSF1 accelerates disease progression in the SOD1G37R mouse, suggesting that overactivation of CSF1R exerts detrimental actions in ALS, probably, by increasing the mitogenic activity of microglia[18,19]. It is important to establish whether pathological activation of CSF1R in ALS contributes to disease progression, and if so, which are the physiological mechanisms underlying its harmful effects, since CSF1 is increased in the spinal cord of ALS patients[19]. We provide evidence that blocking CSF1R ameliorates the clinical course of ALS disease by reducing both the invasion of macrophages into peripheral nerves at pre-symptomatic stages of the disease, and by impeding microglia proliferation at late stages of the pathology

Methods

Results

Conclusion