1. IRAK1 Duplication in MECP2 Duplication Syndrome Does Not Increase Canonical NF-κB-Induced Inflammation
- Author
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Ilona Gottschalk, Uwe Kölsch, Dimitrios L. Wagner, Jonas Kath, Stefania Martini, Renate Krüger, Anne Puel, Jean-Laurent Casanova, Aleksandra Jezela-Stanek, Rainer Rossi, Salima El Chehadeh, Hilde Van Esch, and Horst von Bernuth
- Subjects
Science & Technology ,DE-NOVO-MECP2 DUPLICATION ,CLINICAL-FEATURES ,Immunology ,FUNCTIONAL DISOMY ,Xq28 Duplication syndrome ,Inborn errors of immunity ,INCLUDING MECP2 ,Methyl CpG binding protein 2 (MECP2) ,MENTAL-RETARDATION SYNDROME ,INHERITED DUPLICATION ,GENE DUPLICATION ,Methyl CpG binding protein 2 (MECP2) duplication syndrome ,COPY-NUMBER ,X-CHROMOSOME ,Canonical NF-kappa B signaling ,EPILEPTIC SPASMS ,Immunology and Allergy ,Interleukin-1 receptor-associated kinase 1 (IRAK1) ,Life Sciences & Biomedicine - Abstract
Abstract Purpose Besides their developmental and neurological phenotype, most patients with MECP2/IRAK1 duplication syndrome present with recurrent and severe infections, accompanied by strong inflammation. Respiratory infections are the most common cause of death. Standardized pneumological diagnostics, targeted anti-infectious treatment, and knowledge of the underlying pathomechanism that triggers strong inflammation are unmet clinical needs. We investigated the influence of IRAK1 overexpression on the canonical NF-κB signaling as a possible cause for excessive inflammation in these patients. Methods NF-κB signaling was examined by measuring the production of proinflammatory cytokines and evaluating the IRAK1 phosphorylation and degradation as well as the IκBα degradation upon stimulation with IL-1β and TLR agonists in SV40-immortalized fibroblasts, PBMCs, and whole blood of 9 patients with MECP2/IRAK1 duplication syndrome, respectively. Results Both, MECP2/IRAK1-duplicated patients and healthy controls, showed similar production of IL-6 and IL-8 upon activation with IL-1β and TLR2/6 agonists in immortalized fibroblasts. In PBMCs and whole blood, both patients and controls had a similar response of cytokine production after stimulation with IL-1β and TLR4/2/6 agonists. Patients and controls had equivalent patterns of IRAK1 phosphorylation and degradation as well as IκBα degradation upon stimulation with IL-1β. Conclusion Patients with MECP2/IRAK1 duplication syndrome do not show increased canonical NF-κB signaling in immortalized fibroblasts, PBMCs, and whole blood. Therefore, we assume that these patients do not benefit from a therapeutic suppression of this pathway.
- Published
- 2022