Decreased expression of the fractalkine receptor CX3CR1 on circulating monocytes as new feature of sepsis-induced immunosuppression.
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.
Pachot
Alexandre
A
Joint Unit Hospices Civils de Lyon-bioMérieux, Hôpital Edouard Herriot, 5 place d'Arsonval, Lyon, France.
Cazalis
Marie-Angélique
MA
Venet
Fabienne
F
Turrel
Fanny
F
Faudot
Caroline
C
Voirin
Nicolas
N
Diasparra
Jennifer
J
Bourgoin
Naïck
N
Poitevin
Françoise
F
Mougin
Bruno
B
Lepape
Alain
A
Monneret
Guillaume
G
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
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