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Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

Authors
  • Della Mina, Erika
  • Borghesi, Alessandro
  • Zhou, Hao
  • Bougarn, Salim
  • Boughorbel, Sabri
  • Israel, Laura
  • Meloni, Ilaria
  • Chrabieh, Maya
  • Ling, Yun
  • Itan, Yuval
  • Renieri, Alessandra
  • Mazzucchelli, Iolanda
  • Basso, Sabrina
  • Pavone, Piero
  • Falsaperla, Raffaele
  • Ciccone, Roberto
  • Cerbo, Rosa Maria
  • Stronati, Mauro
  • Picard, Capucine
  • Zuffardi, Orsetta
  • And 6 more
Type
Published Article
Journal
Proceedings of the National Academy of Sciences
Publisher
Proceedings of the National Academy of Sciences
Publication Date
Jul 11, 2017
Volume
114
Issue
4
Identifiers
DOI: 10.1073/pnas.1620139114
PMID: 28069966
PMCID: PMC5278481
Source
USPC - SET - SVS
License
Green

Abstract

Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1 Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4- or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient's fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient's peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.

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