title: LRRK2 modulates microglial activity through regulation of chemokine (C-X3-C) receptor 1 -mediated signalling pathways.
abstract: Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) have been linked to Parkinson's disease (PD), the most common degenerative movement disorder. LRRK2 is expressed by both neurons and microglia, the residential immune cells in the brain. Increasing evidence supports a role of LRRK2 in modulating microglial activity, of which Lrrk2-null rodent microglia display less inflammatory response to endotoxin lipopolysaccharide (LPS). The underlying molecular mechanism, however, remains elusive. Chemokine (C-X3-C) receptor 1 (CX3CR1), predominantly expressed by microglia, suppresses microglial inflammation while promotes migration. Using whole-genome microarray screening, we found that Cx3cr1 mRNA levels were substantially higher in microglia derived from Lrrk2 knockout (Lrrk2-/-) mice. The total and cell surface levels of CX3CR1 proteins were also remarkably increased. In correlation with the enhanced CX3CR1 expression, Lrrk2-null microglia migrated faster and travelled longer distance toward the source of fractalkine (CX3CL1), an endogenous ligand of CX3CR1. To investigate the impact of CX3CR1 elevation in vivo, we compared LPS-induced inflammation in the striatum of Lrrk2-/-knockout mice with Cx3cr1 heterozygous and homozygous knockout background. We found that a complete loss of Cx3cr1 restored the responsiveness of Lrrk2-/-microglia to LPS stimulation. In conclusion, our findings reveal a previously unknown regulatory role for LRRK2 in CX3CR1 signalling and suggest that an increase of CX3CR1 activity contributes to the attenuated inflammatory responses in Lrrk2-null microglia.
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.affiliation: Division of Neuropathology, Department of pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Leyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Pan
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Bioinformatics Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.affiliation: Division of Neuropathology, Department of pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA caih@mail.nih.gov.
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008262:Macrophage Activation / Q000187:drug effects; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2