title: Decreased expression of the fractalkine receptor CX3CR1 on circulating monocytes as new feature of sepsis-induced immunosuppression.
abstract: Although it is known that septic shock rapidly induces immune dysfunctions, which contribute to the impaired clearance of microorganisms observed in patients, the mechanisms for this phenomenon remain incompletely understood. We recently observed, in a microarray study, an altered circulating leukocyte CX3CR1 mRNA expression associated with patients' mortality. As monocytes play a central role in septic shock pathophysiology and express high levels of CX3CR1, we therefore further investigated the alteration of CX3CR1 expression and of its ligand fractalkine (CX3CL1) on those cells in this clinical condition. We observed that CX3CR1 expression (both mRNA and protein) was severely down-regulated in monocytes and consequently associated with a lack of functionality upon fractalkine challenge. Importantly, nonsurvivors presented with significantly sustained lower expression in comparison with survivors. This down-regulation was reproduced by incubation of cells from healthy individuals with LPS, whole bacteria (Escherichia coli and Staphylococcus aureus), and, to a lower extent, with corticosteroids-in accordance with the concept of LPS-induced monocyte deactivation. In addition, CX3CL1 serum concentrations were elevated in patients supporting the hypothesis of increased cleavage of the membrane-anchored form expressed by endothelial cells. As CX3CR1/CX3CL1 interaction preferentially mediates arrest and migration of proinflammatory cells, the present observations may contribute to patients' inability to kill invading microorganisms. This could represent an important new feature of sepsis-induced immunosuppression.
authors.affiliation: Joint Unit Hospices Civils de Lyon-bioMérieux, Hôpital Edouard Herriot, 5 place d'Arsonval, Lyon, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Pachot
authors.forename: Marie-Angélique
authors.initials: MA
authors.lastname: Cazalis
authors.forename: Fabienne
authors.initials: F
authors.lastname: Venet
authors.forename: Fanny
authors.initials: F
authors.lastname: Turrel
authors.forename: Caroline
authors.initials: C
authors.lastname: Faudot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Voirin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Diasparra
authors.forename: Naïck
authors.initials: N
authors.lastname: Bourgoin
authors.forename: Françoise
authors.initials: F
authors.lastname: Poitevin
authors.forename: Bruno
authors.initials: B
authors.lastname: Mougin
authors.forename: Alain
authors.initials: A
authors.lastname: Lepape
authors.forename: Guillaume
authors.initials: G
authors.lastname: Monneret
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054428:Chemokine CX3CL1 / Q000097:blood / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000097:blood / Q000276:immunology; D019707:Receptors, Chemokine / Q000097:blood* / Q000276:immunology; D012772:Shock, Septic / Q000097:blood* / Q000276:immunology / Q000473:pathology; D013211:Staphylococcus aureus
chemical_list: D000305:Adrenal Cortex Hormones; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019707:Receptors, Chemokine