TY - JOUR
T1 - Toll-like receptors expression and interferon-γ production by NK cells in human sepsis
AU - Souza-Fonseca-Guimaraes, Fernando
AU - Parlato, Marianna
AU - Philippart, François
AU - Misset, Benoît
AU - Cavaillon, Jean Marc
AU - Adib-Conquy, Minou
AU - Jacqmin, Sébastien
AU - Journois, Didier
AU - Lagrange, Alix
AU - de Villechenon, Gabrielle Pinot
AU - Aissaoui, Nadia
AU - Diehl, Jean Luc
AU - Guerot, Emmanuel
AU - Venot, Marion
AU - Hamzaoui, Olfa
AU - Prat, Dominique
AU - Sztrymf, Benjamin
AU - Maxime, Djillali Annane Virginie
AU - Polito, Andrea
AU - Bournaud, Elsa
AU - Bruel, Cédric
AU - Fournier, Julien
AU - Garrouste-Orgeas, Maïté
AU - Gregoire, Charles
AU - Lau, Nicolas
AU - Max, Adeline
AU - Bouhemad, Belaïd
AU - Ethuin, Frédéric
AU - Bedos, Jean Pierre
AU - Crosnier, Pierrick
AU - Laurent, Virginie
AU - Merceron, Sybille
AU - Pachot, Alexandre
AU - Moucadel, Virginie
N1 - Funding Information:
The authors thank Kathryn Rozen-Gagnon for English editing of the manuscript. This work is part of the CAPTAIN STUDY supported by the Programme Hospitalier de Recherche Clinique (PHRC) and by the Biomérieux-Institut Pasteur collaborative research program. This project is part of Advanced Diagnostics for New Therapeutic Approaches, a program dedicated to personalized medicine, coordinated by Mérieux Alliance and supported by the French public agency, OSEO. FSFG was funded by the international PhD program of Institut Pasteur and Paris University and a Pasteur-Weizmann fellowship. The CAPTAIN study group is composed of: Sébastien Jacqmin, Didier Journois, Alix Lagrange, Gabrielle Pinot de Villechenon (Hôpital Européen Georges Pompidou, AP - HP - Université Paris Descartes, Service d’Anesthésie-Réanimation), Nadia Aissaoui, Jean-Luc Diehl, Emmanuel Guerot, Marion Venot (Hôpital Européen Georges Pompidou, AP - HP - Université Paris Descartes, Service de Réanimation Médicale), Olfa Hamzaoui, Dominique Prat, Benjamin Sztrymf (Hôpital Antoine Béclère, AP - HP - Université Paris Sud, Clamart), Djillali Annane Virginie Maxime, Andrea Polito (Hôpital Raymond Poincaré, AP - HP - Université Paris Ile de France Ouest, Service de Réanimation Médico-chirurgicale), Elsa Bournaud, Cédric Bruel, Julien Fournier, Maïté Garrouste-Orgeas, Charles Gregoire, Nicolas Lau, Adeline Max, Benoît Misset, François Philippart (Groupe Hospitalier Paris Saint Joseph - Université Paris Descartes, Service de Réanimation polyvalente), Belaïd Bouhemad, Frédéric Ethuin (Groupe Hospitalier Paris Saint Joseph, Service de Réanimation chirurgicale), Jean-Pierre Bedos, Pierrick Crosnier, Virginie Laurent, Sybille Merceron (Hôpital André Mignot, Versailles, Service de Réanimation médico-chirurgicale), Alexandre Pachot, Virginie Moucadel (Biomérieux, Marcy-l’Etoile).
PY - 2012/10/25
Y1 - 2012/10/25
N2 - Introduction: During the course of infection, natural killer (NK) cells contribute to innate immunity by producing cytokines, particularly interferon-gamma (IFN-γ). In addition to their beneficial effects against infection, NK cells may play a detrimental role during systemic inflammation, causing lethality during sepsis. Little is known on the immune status of NK cells in patients with systemic inflammatory response syndrome (SIRS) or sepsis in terms of cell surface markers expression and IFN-γ production.Methods: We investigated 27 sepsis patients and 11 patients with non-infectious SIRS. CD56bright and CD56dim NK cell subsets were identified by flow cytometry and Toll-like receptor (TLR)2, TLR4, TLR9, CX3CR1, CD16 and CD69 expression were analyzed, as well as ex vivo IFN-γ production by NK cells in whole blood samples.Results: We first showed that in NK cells from healthy controls, TLR2 and TLR4 expression is mainly intracellular, similarly to TLR9. Intracellular levels of TLR2 and TLR4, in both CD56bright and CD56dim NK cell subsets from sepsis patients, were increased compared to healthy subjects. In addition, the percentage of CD69+ cells was higher among NK cells of sepsis patients. No difference was observed for TLR9, CX3CR1, and CD16 expression. The ex vivo stimulation by TLR4 or TLR9 agonists, or whole bacteria in synergy with accessory cytokines (IL-15+IL-18), resulted in significant production of IFN-γ by NK cells of healthy controls. In contrast, for SIRS and sepsis patients this response was dramatically reduced.Conclusions: This study reports for the first time an intracellular expression of TLR2 and TLR4 in human NK cells. Surface TLR4 expression allows discriminating sepsis and SIRS. Furthermore, during these pathologies, NK cells undergo an alteration of their immune status characterized by a profound reduction of their capacity to release IFN-γ.
AB - Introduction: During the course of infection, natural killer (NK) cells contribute to innate immunity by producing cytokines, particularly interferon-gamma (IFN-γ). In addition to their beneficial effects against infection, NK cells may play a detrimental role during systemic inflammation, causing lethality during sepsis. Little is known on the immune status of NK cells in patients with systemic inflammatory response syndrome (SIRS) or sepsis in terms of cell surface markers expression and IFN-γ production.Methods: We investigated 27 sepsis patients and 11 patients with non-infectious SIRS. CD56bright and CD56dim NK cell subsets were identified by flow cytometry and Toll-like receptor (TLR)2, TLR4, TLR9, CX3CR1, CD16 and CD69 expression were analyzed, as well as ex vivo IFN-γ production by NK cells in whole blood samples.Results: We first showed that in NK cells from healthy controls, TLR2 and TLR4 expression is mainly intracellular, similarly to TLR9. Intracellular levels of TLR2 and TLR4, in both CD56bright and CD56dim NK cell subsets from sepsis patients, were increased compared to healthy subjects. In addition, the percentage of CD69+ cells was higher among NK cells of sepsis patients. No difference was observed for TLR9, CX3CR1, and CD16 expression. The ex vivo stimulation by TLR4 or TLR9 agonists, or whole bacteria in synergy with accessory cytokines (IL-15+IL-18), resulted in significant production of IFN-γ by NK cells of healthy controls. In contrast, for SIRS and sepsis patients this response was dramatically reduced.Conclusions: This study reports for the first time an intracellular expression of TLR2 and TLR4 in human NK cells. Surface TLR4 expression allows discriminating sepsis and SIRS. Furthermore, during these pathologies, NK cells undergo an alteration of their immune status characterized by a profound reduction of their capacity to release IFN-γ.
UR - http://www.scopus.com/inward/record.url?scp=84867740346&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867740346&partnerID=8YFLogxK
U2 - 10.1186/cc11838
DO - 10.1186/cc11838
M3 - Article
C2 - 23098236
AN - SCOPUS:84867740346
VL - 16
JO - Critical Care
JF - Critical Care
SN - 1364-8535
IS - 5
M1 - R206
ER -