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 fourmolecules, 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 areweak but not abolished inmice 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. Unlikemost 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 fromthe 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.
| Original language | English |
|---|---|
| Pages (from-to) | E514-E523 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 114 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 24 Jan 2017 |
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Keywords
- Interleukin-1 receptor
- IRAK-1
- IRAK-4
- Primary immunodeficiency
- Toll-like receptor
ASJC Scopus subject areas
- General
Cite this
Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts. / Mina, Erika Della; 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; Abel, Laurent; Chaussabel, Damien J.; Marr, Nico; Li, Xiaoxia; Casanova, Jean Laurent; Puel, Anne.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 4, 24.01.2017, p. E514-E523.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts
AU - Mina, Erika Della
AU - Borghesi, Alessandro
AU - Zhou, Hao
AU - Bougarn, Salim
AU - Boughorbel, Sabri
AU - Israel, Laura
AU - Meloni, Ilaria
AU - Chrabieh, Maya
AU - Ling, Yun
AU - Itan, Yuval
AU - Renieri, Alessandra
AU - Mazzucchelli, Iolanda
AU - Basso, Sabrina
AU - Pavone, Piero
AU - Falsaperla, Raffaele
AU - Ciccone, Roberto
AU - Cerbo, Rosa Maria
AU - Stronati, Mauro
AU - Picard, Capucine
AU - Zuffardi, Orsetta
AU - Abel, Laurent
AU - Chaussabel, Damien J.
AU - Marr, Nico
AU - Li, Xiaoxia
AU - Casanova, Jean Laurent
AU - Puel, Anne
PY - 2017/1/24
Y1 - 2017/1/24
N2 - 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 fourmolecules, 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 areweak but not abolished inmice 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. Unlikemost 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 fromthe 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.
AB - 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 fourmolecules, 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 areweak but not abolished inmice 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. Unlikemost 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 fromthe 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.
KW - Interleukin-1 receptor
KW - IRAK-1
KW - IRAK-4
KW - Primary immunodeficiency
KW - Toll-like receptor
UR - http://www.scopus.com/inward/record.url?scp=85010936513&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85010936513&partnerID=8YFLogxK
U2 - 10.1073/pnas.1620139114
DO - 10.1073/pnas.1620139114
M3 - Article
VL - 114
SP - E514-E523
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 4
ER -