title: Inflammatory dysregulation of blood monocytes in Parkinson's disease patients.
abstract: Despite extensive effort on studying inflammatory processes in the CNS of Parkinson's disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte-recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a "second hit". These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation.
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Veselin
authors.initials: V
authors.lastname: Grozdanov
authors.forename: Corinna
authors.initials: C
authors.lastname: Bliederhaeuser
authors.forename: Wolfgang P
authors.initials: WP
authors.lastname: Ruf
authors.forename: Valerie
authors.initials: V
authors.lastname: Roth
authors.forename: Kathrin
authors.initials: K
authors.lastname: Fundel-Clemens
authors.forename: Lisa
authors.initials: L
authors.lastname: Zondler
authors.forename: David
authors.initials: D
authors.lastname: Brenner
authors.forename: Ana
authors.initials: A
authors.lastname: Martin-Villalba
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.forename: Jan
authors.initials: J
authors.lastname: Kassubek
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D015331:Cohort Studies; D003470:Culture Media / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology*; D010300:Parkinson Disease / Q000150:complications* / Q000473:pathology*; D010587:Phagocytosis; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D018932:Chemokine CCL2; D003470:Culture Media; D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger