Ankyrin repeat domain 1 regulates innate immune responses against herpes simplex virus 1: A potential role in eczema herpeticum - 06/06/18
Abstract |
Background |
Atopic dermatitis (AD) is a common inflammatory skin disease. A subset of patients with AD are susceptible to disseminated herpes simplex virus (HSV) infection, a complication termed eczema herpeticum (ADEH+). The immune mechanisms causing ADEH+ remain elusive. Using RNA sequencing, we recently found that ankyrin repeat domain 1 (ANKRD1) was significantly induced in human PBMCs upon HSV-1 stimulation, and its induction in patients with ADEH+ was significantly reduced compared with that seen in AD patients without a history of eczema herpeticum (ADEH−).
Objective |
We sought to validate ANKRD1 gene expression in nonatopic (NA) subjects, patients with ADEH−, and patients with ADEH+ and to delineate the biological function of ANKRD1 and the signaling pathway or pathways involved.
Methods |
Purification of human PBMCs, monocytes, B cells, dendritic cells, T cells, and natural killer cells; RNA extraction and quantitative RT-PCR; small interfering RNA technique; co-immunoprecipitation; and Western blot assays were used.
Results |
ANKRD1 expression was significantly reduced in PBMCs from patients with ADEH+ after HSV-1 stimulation compared with PBMCs from patients with ADEH−. We found that the induction of ANKRD1 by HSV-1 and multiple pattern recognition receptor agonists are mediated by inflammatory cytokines. Silencing ANKRD1 gene expression in antigen-presenting cells led to increased viral load and reduced IFNB1 and IL29 production. Using co-immunoprecipitation methods, we demonstrated that ANKRD1 formed protein complexes with interferon regulatory factor (IRF) 3 and IRF7, which are important transcription factors regulating signaling transduction of pattern recognition receptors. Overexpression of ANKRD1 enhanced the IRF3-mediated signaling pathways.
Conclusion |
ANKRD1 is involved in IRF3-mediated antiviral innate immune signaling pathways. Its reduced expression in patients with ADEH+ might contribute to the pathogenesis of ADEH+.
Le texte complet de cet article est disponible en PDF.Key words : Herpes simplex virus, ankyrin repeat domain 1, innate immunity, atopic dermatitis, eczema herpeticum, interferon regulatory 3, nuclear factor κB1, IFN-β1, IL-29
Abbreviations used : AD, ADEH+, ADEH−, ANKRD1, APC, HA, HCV, HPV, HSV, IRF, MOI, NA, NF-κB, NK, Poly dA:dT, Poly I:C-LMW, PRR, qRT-PCR, siRNA, TLR
Plan
| Supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases through the Atopic Dermatitis Research Network (U19 AI117673). L.B. is also supported by National Natural Science Foundation of China (no. 81371716) and 111 project (B16021). The CTRC is supported in part by the Colorado Clinical and Translational Science Award/Colorado Clinical & Translational Sciences Institute grant UL1 RR025780 from National Center for Research Resources/National Institutes of Health (NIH) and UL1 TR0001082 from the NIH/National Center for Advancing Translational Sciences. Additionally, the authors wish to acknowledge the Edelstein Family Foundation for their generous support of our work. |
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| Disclosure of potential conflict of interest: P. Taylor and D. Y. M. Leung indicate that the work was supported by the National Institute of Allergy and Infectious Diseases/National Institute of Health–funded Atopic Dermatitis Research Network (1U19Al117673). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 6
P. 2085 - juin 2018 Retour au numéro
Article précédent
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