title: CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves.
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 SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) 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 SOD1(G93A) 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.
authors.affiliation: Institut de Neurociencies, Department Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Martínez-Muriana
authors.affiliation: Institut de Neurociencies, Department Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Renzo
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Institut de Neurociencies, Department Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Francos-Quijorna
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD United Kingdom.
authors.forename: Adrian
authors.initials: A
authors.lastname: Olmos-Alonso
authors.affiliation: Laboratory of Genetic Biochemistry (LAGENBIO), Health Research Institute of Aragón, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Osta
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD United Kingdom.
authors.forename: V Hugh
authors.initials: VH
authors.lastname: Perry
authors.affiliation: Institut de Neurociencies, Department Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
authors.affiliation: Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD United Kingdom.
authors.forename: Diego
authors.initials: D
authors.lastname: Gomez-Nicola
authors.affiliation: Institut de Neurociencies, Department Biologia Cellular, Fisiologia i Immunologia, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Bellaterra, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: López-Vales
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D005911:Gliosis / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism; D010525:Peripheral Nerves / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; C000604004:Csf1r protein, mouse; D011743:Pyrimidines; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase