CSF1R signaling is a regulator of pathogenesis in progressive MS.
Animals
Cell Proliferation
/ drug effects
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental
/ pathology
Humans
Inflammation
/ pathology
Macrophages
/ drug effects
Mice
Microglia
/ pathology
Multiple Sclerosis
/ metabolism
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
/ metabolism
Signal Transduction
/ drug effects
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
23 10 2020
23 10 2020
Historique:
received:
20
05
2020
accepted:
01
10
2020
revised:
30
09
2020
entrez:
24
10
2020
pubmed:
25
10
2020
medline:
14
5
2021
Statut:
epublish
Résumé
Microglia serve as the innate immune cells of the central nervous system (CNS) by providing continuous surveillance of the CNS microenvironment and initiating defense mechanisms to protect CNS tissue. Upon injury, microglia transition into an activated state altering their transcriptional profile, transforming their morphology, and producing pro-inflammatory cytokines. These activated microglia initially serve a beneficial role, but their continued activation drives neuroinflammation and neurodegeneration. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, and activated microglia and macrophages play a significant role in mediating disease pathophysiology and progression. Colony-stimulating factor-1 receptor (CSF1R) and its ligand CSF1 are elevated in CNS tissue derived from MS patients. We performed a large-scale RNA-sequencing experiment and identified CSF1R as a key node of disease progression in a mouse model of progressive MS. We hypothesized that modulating microglia and infiltrating macrophages through the inhibition of CSF1R will attenuate deleterious CNS inflammation and reduce subsequent demyelination and neurodegeneration. To test this hypothesis, we generated a novel potent and selective small-molecule CSF1R inhibitor (sCSF1R
Identifiants
pubmed: 33097690
doi: 10.1038/s41419-020-03084-7
pii: 10.1038/s41419-020-03084-7
pmc: PMC7584629
doi:
Substances chimiques
CSF1R protein, human
0
Csf1r protein, mouse
0
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
904Subventions
Organisme : NINDS NIH HHS
ID : R01 NS088137
Pays : United States
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