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Decreased Expression of the Fractalkine Receptor CX3CR1 on Circulating Monocytes as New Feature of Sepsis-Induced Immunosuppression

Alexandre Pachot^*, Marie-Angélique Cazalis^*, Fabienne Venet, Fanny Turrel^*, Caroline Faudot^*, Nicolas Voirin, Jennifer Diasparra^*, Naïck Bourgoin^*, Françoise Poitevin, Bruno Mougin^*, Alain Lepape and Guillaume Monneret^1,

^* Joint Unit Hospices Civils de Lyon-bioMérieux and Department of Public Health, Epidemiology and Prevention, Hôpital Edouard Herriot, Lyon; Flow Cytometry Unit, Immunology department, Hôpital Neurologique, Lyon; and Intensive Care Unit, Centre Hospitalier Lyon-Sud, Pierre Bénite, France

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Guillaume Monneret, Hôpital Edouard Herriot, 5 place d’Arsonval, 69003 Lyon, France. E-mail address: guillaume.monneret{at}chu-lyon.fr

² Abbreviations used in this paper: s, soluble; PPIB, peptidylpropyl isomerase B; MFI, mean fluorescence intensity; mHLA-DR, monocyte HLA-DR; SAPS II, simplified acute physiologic score II; ICU, intensive care unit.