Granulocyte colony stimulating factor attenuates inflammation in a mouse model of amyotrophic lateral sclerosis.

Eveliina Pollari,Merja Jaronen,Rashid Giniatullin,Sara Wojciechowski,Raisa Giniatullina,Ekaterina Savchenko,Johanna Magga,Katja Kanninen,Jari Koistinaho,Toni Ahtoniemi,Tarja Malm,Gundars Goldsteins

doi:10.1186/1742-2094-8-74

Abstract

BackgroundGranulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases. We investigated whether pegfilgrastim, GCSF with sustained action, is protective in a mouse model of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery.MethodsHuman mutant G93A superoxide dismutase (SOD1) ALS mice were treated with pegfilgrastim starting at the presymptomatic stage and continued until the end stage. After long-term pegfilgrastim treatment, the inflammation status was defined in the spinal cord and peripheral tissues including hematopoietic organs and muscle. The effect of GCSF on spinal cord neuron survival and microglia, bone marrow and spleen monocyte activation was assessed in vitro.ResultsLong-term pegfilgrastim treatment prolonged mutant SOD1 mice survival and attenuated both astro- and microgliosis in the spinal cord. Pegfilgrastim in SOD1 mice modulated the inflammatory cell populations in the bone marrow and spleen and reduced the production of pro-inflammatory cytokine in monocytes and microglia. The mobilization of hematopoietic stem cells into the circulation was restored back to basal level after long-term pegfilgrastim treatment in SOD1 mice while the storage of Ly6C expressing monocytes in the bone marrow and spleen remained elevated. After pegfilgrastim treatment, an increased proportion of these cells in the degenerative muscle was detected at the end stage of ALS.ConclusionsGCSF attenuated inflammation in the CNS and the periphery in a mouse model of ALS and thereby delayed the progression of the disease. This mechanism of action targeting inflammation provides a new perspective of the usage of GCSF in the treatment of ALS.

Highlights

Granulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases
GCSF with sustained activity prolongs the survival of superoxide dismutase1 (SOD1) mice We first determined the plasma concentrations of GCSF in mutant SOD1 mice after administration of pegfilgrastim
Even though GCSF has a moderate effect on mutant SOD1 mouse survival, as we describe in this study, the GCSF-mediated effects on the modulation of inflammation are interesting and highly relevant in the light of amyotrophic lateral sclerosis (ALS) pathology

Summary

Introduction

Granulocyte colony stimulating factor (GCSF) is protective in animal models of various neurodegenerative diseases. ALS is a fatal neurodegenerative disease with manifestations of upper and lower motoneuron death and muscle atrophy accompanied by inflammation in the CNS and periphery. ALS is a neurodegenerative disorder leading to progressive upper and lower motoneuron decline, muscle atrophy and death within a few years from diagnosis [1]. One of the mutations causing familial ALS occurs in the copper/zinc (Cu/Zn) superoxide dismutase. Since the clinical and pathological nature of familial and sporadic ALS are similar, mechanisms of mutant SOD1 toxicity are thought to elucidate the disease mechanisms in sporadic ALS. Transgenic animal models expressing mutant SOD1 have been widely used to study ALS pathogenesis [3]

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