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

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves
CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves
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.
1-13
Martinez-Muriana, Anna
ed3b4f33-d608-4d10-94ed-99b6337efd6e
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Francos-Quijorna, Isaac
a6f10a12-1236-4f45-ad01-d3f83a21ba1c
Olmos-Alonso, Adrian
c52c3bd9-2cf0-4b55-9214-cb549449db75
Osta, Rosario
64007891-e6c1-4242-ab1c-0c5e69276431
Perry, Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Navarro, Xavier
8854ebaa-d283-4d46-829e-c7c8f186585e
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Lopez-Vales, Ruben
c88d54d9-07a1-46d0-aef9-743e930c62a0
Martinez-Muriana, Anna
ed3b4f33-d608-4d10-94ed-99b6337efd6e
Mancuso, Renzo
05786562-a993-4e37-926e-3c1fcf50b36d
Francos-Quijorna, Isaac
a6f10a12-1236-4f45-ad01-d3f83a21ba1c
Olmos-Alonso, Adrian
c52c3bd9-2cf0-4b55-9214-cb549449db75
Osta, Rosario
64007891-e6c1-4242-ab1c-0c5e69276431
Perry, Hugh
8f29d36a-8e1f-4082-8700-09483bbaeae4
Navarro, Xavier
8854ebaa-d283-4d46-829e-c7c8f186585e
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Lopez-Vales, Ruben
c88d54d9-07a1-46d0-aef9-743e930c62a0

Martinez-Muriana, Anna, Mancuso, Renzo, Francos-Quijorna, Isaac, Olmos-Alonso, Adrian, Osta, Rosario, Perry, Hugh, Navarro, Xavier, Gomez-Nicola, Diego and Lopez-Vales, Ruben (2016) CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves. Scientific Reports, 6 (25663), 1-13. (doi:10.1038/srep25663). (PMID:27174644)

Record type: Article

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.

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Accepted/In Press date: 20 April 2016
e-pub ahead of print date: 13 May 2016
Organisations: Biomedicine

Identifiers

Local EPrints ID: 394367
URI: https://eprints.soton.ac.uk/id/eprint/394367
PURE UUID: 09f42a10-a85d-4263-8d93-f96405f37435
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

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Date deposited: 18 May 2016 10:25
Last modified: 06 Jun 2018 12:33

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