TLR9 activation induces normal neutrophil responses in a child with IRAK-4 deficiency: involvement of the direct PI3K pathway.
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.
Hoarau
Cyrille
C
Unité de Formation et de Recherche de Médecine, Cellules Dendritiques et Greffes, Université François Rabelais, Tours, France.
Gérard
Bénédicte
B
Lescanne
Emmanuel
E
Henry
Dominique
D
François
Stéphanie
S
Lacapère
Jean-Jacques
JJ
El Benna
Jamel
J
Dang
Pham My-Chan
PM
Grandchamp
Bernard
B
Lebranchu
Yvon
Y
Gougerot-Pocidalo
Marie-Anne
MA
Elbim
Carole
C
D000293:Adolescent; D001483:Base Sequence; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D020382:Interleukin-18 / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism*
D007375:Interleukin-1; D020382:Interleukin-18; D017382:Reactive Oxygen Species; D051217:Toll-Like Receptor 9; D019869:Phosphatidylinositol 3-Kinases; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases