title: Parkinson's disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures.
abstract: Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson's disease (PD), Crohn's disease and leprosy. As all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions. Here, we report that full-length Lrrk2 is a relatively common constituent of human peripheral blood mononuclear cells (PBMC) including affinity isolated, CD14(+) monocytes, CD19(+) B cells, and CD4(+) as well as CD8(+) T cells. Up to 26% of PBMC from healthy donors and up to 43% of CD14(+) monocytes were stained by anti-Lrrk2 antibodies using cell sorting. PBMC lysates contained full-length (>260 kDa) and higher molecular weight Lrrk2 species. The expression of LRRK2 in circulating leukocytes was confirmed by microscopy of human blood smears and in sections from normal midbrain and distal ileum. Lrrk2 reactivity was also detected in mesenteric lymph nodes and spleen (including in dendritic cells), but was absent in splenic mononuclear cells from lrrk2-null mice, as expected. In cultured bone marrow-derived macrophages from mice we made three observations: (i) a predominance of higher molecular weight lrrk2; (ii) the reduction of autophagy marker LC3-II in (R1441C)lrrk2-mutant cells (<31%); and (iii) a significant up-regulation of lrrk2 mRNA (>fourfold) and protein after exposure to several microbial structures including bacterial lipopolysaccharide and lentiviral particles. We conclude that Lrrk2 is a constituent of many cell types in the immune system. Following the recognition of microbial structures, stimulated macrophages respond with altered lrrk2 gene expression. In the same cells, lrrk2 appears to co-regulate autophagy. A pattern recognition receptor-type function for LRRK2 could explain its locus' association with Crohn's disease and leprosy risk. We speculate that the role of Lrrk2 in immune cells may also be relevant to the susceptibility of developing PD or its progression.
authors.affiliation: Division of Neuroscience, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Hakimi
authors.forename: Thirumahal
authors.initials: T
authors.lastname: Selvanantham
authors.forename: Erika
authors.initials: E
authors.lastname: Swinton
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Padmore
authors.forename: Youren
authors.initials: Y
authors.lastname: Tong
authors.forename: Ghassan
authors.initials: G
authors.lastname: Kabbach
authors.forename: Katerina
authors.initials: K
authors.lastname: Venderova
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Scherzer
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaVoie
authors.forename: Denis
authors.initials: D
authors.lastname: Gris
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Angel
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D001343:Autophagy / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D007962:Leukocytes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases