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The Journal of Immunology, 2005, 174: 3633-3642.
Copyright © 2005 by The American Association of Immunologists

Inhibition of Neutrophil Apoptosis by TLR Agonists in Whole Blood: Involvement of the Phosphoinositide 3-Kinase/Akt and NF-{kappa}B Signaling Pathways, Leading to Increased Levels of Mcl-1, A1, and Phosphorylated Bad

Stéphanie François*,{dagger}, Jamel El Benna*, Pham M. C. Dang*, Eric Pedruzzi*, Marie-Anne Gougerot-Pocidalo1,*,{dagger} and Carole Elbim*,{dagger}

* Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 479, Faculté Xavier Bichat, and {dagger} Service d’Immunologie et d’Hématologie, Centre Hospitalo-Universitaire Xavier Bichat, Paris, France

Using flow cytometry, we investigated the effect of TLR agonists on human polymorphonuclear neutrophil (PMN) apoptosis in whole blood. LPS (TLR4), peptidoglycan (TLR2), R-848 (TLR7/8), and CpG-DNA (TLR9) were equally effective at delaying spontaneous apoptosis of PMN, while PamCSK4 (TLR1/2), macrophage-activating lipopeptide-2 (TLR2/6), flagellin (TLR5), and loxoribine (TLR7) were less effective or inactive. TLR agonists found to delay apoptosis also extended the functional life span of PMN. Analysis of signaling pathways revealed that the antiapoptotic effect of TLR agonists required NF-{kappa}B and PI3K activation. Furthermore, analysis of intact cells by flow cytometry showed that TLR agonists delaying PMN apoptosis increased phosphorylation of Akt, a major target of PI3K. This effect was associated with a PI3K-dependent increase in heat shock protein 27 phosphorylation, which has been reported to play a key role in PMN survival. Finally, the TLR-induced delay in PMN apoptosis was associated with increased levels of Mcl-1 and A1, which are antiapoptotic members of the Bcl-2 family. These effects were reversed by PI3K and NF-{kappa}B inhibitors, respectively. TLR activation also led to PI3K-dependent phosphorylation of the proapoptotic protein Bad. Taken together, our results strongly suggest a role of NF-{kappa}B and PI3K in TLR-induced PMN survival, leading to modulation of Bcl-2 family molecules.




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