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TLR9 Activation Induces Normal Neutrophil Responses in a Child with IRAK-4 Deficiency: Involvement of the Direct PI3K Pathway

Cyrille Hoarau^*,, Bénédicte Gérard^,, Emmanuel Lescanne, Dominique Henry, Stéphanie François^,,¶, Jean-Jacques Lacapère^,¶, Jamel El Benna^,¶, Pham My-Chan Dang^,¶, Bernard Grandchamp^,, Yvon Lebranchu^*,, Marie-Anne Gougerot-Pocidalo^,,¶ and Carole Elbim^1,,,¶

^* Unité de Formation et de Recherche de Médecine, Cellules Dendritiques et Greffes, Université François Rabelais, Tours, France; Unité Transversale d’Allergologie, Néphrologie et Immunologie Clinique et Service d’Oto-Rhino-Laryngologie, Centre Hospitalier Universitaire de Tours, Tours, France; Faculté de Médecine, site Bichat, Université Paris 7, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d’Immunologie et d’Hématologie et Service de Biochimie Hormonale et Génétique, Centre d’Investigation Biomédical Phenogen, Centre Hospitalier Universitaire Xavier Bichat, Paris, France; and ^¶ Institut National de la Santé et de la Recherche Médicale Unité 773, Paris, France

Polymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg¹²Cys) associated in cis-with a predicted benign variant (pArg³⁹¹His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient’s functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient’s PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient’s PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency.

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. Carole Elbim, Institut National de la Santé et de la Recherche Médicale Unité 773, Faculté Xavier Bichat, 16 rue Henri Huchard, Paris, France. E-mail address: carole.elbim{at}bch.aphp.fr

² Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; ROS, reactive oxygen species; IRAK, interleukin-1 receptor-associated kinase; TIR, Toll-IL-1 receptor; TRAF6, TNFR-associated factor 6; MALP-2, macrophage-activating lipopeptide-2; HE, hydroethidin; 7-AAD, 7-aminoactinomycin D; Pam3CSK4, palmitoylated mimic of bacterial lipopeptides; CBA, cytometric bead array; LNA, locked nucleic acid; MFI, mean fluorescence intensity.