SARS-CoV-2 Infection Induces Psoriatic Arthritis Flares and Enthesis Resident Plasmacytoid Dendritic Cell Type-1 Interferon Inhibition by JAK Antagonism Offer Novel Spondyloarthritis Pathogenesis Insights.
Adjuvants, Immunologic
/ pharmacology
Adult
Aged
Arthritis, Psoriatic
/ complications
COVID-19
/ complications
Computational Biology
Cyclic Nucleotide Phosphodiesterases, Type 4
/ metabolism
Dendritic Cells
/ drug effects
Female
Gene Expression Regulation
/ drug effects
Humans
Imiquimod
/ pharmacology
Interferon-alpha
/ metabolism
Janus Kinases
/ antagonists & inhibitors
Male
Middle Aged
NF-kappa B
/ metabolism
Oligonucleotides
/ pharmacology
Phosphodiesterase 4 Inhibitors
/ pharmacology
Piperidines
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Pyrimidines
/ pharmacology
Signal Transduction
/ drug effects
Toll-Like Receptor 7
/ metabolism
Toll-Like Receptor 9
/ metabolism
Transcriptome
Tumor Necrosis Factor-alpha
/ metabolism
COVID-19
enthesis
interferon alpha
plasmacytoid dendritic cells
psoriatic arthritis
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
29
11
2020
accepted:
08
03
2021
entrez:
3
5
2021
pubmed:
4
5
2021
medline:
15
5
2021
Statut:
epublish
Résumé
Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated. CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection). Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.
Identifiants
pubmed: 33936047
doi: 10.3389/fimmu.2021.635018
pmc: PMC8082065
doi:
Substances chimiques
Adjuvants, Immunologic
0
Interferon-alpha
0
NF-kappa B
0
Oligonucleotides
0
Phosphodiesterase 4 Inhibitors
0
Piperidines
0
Protein Kinase Inhibitors
0
Pyrimidines
0
TLR7 protein, human
0
TLR9 protein, human
0
Toll-Like Receptor 7
0
Toll-Like Receptor 9
0
Tumor Necrosis Factor-alpha
0
tofacitinib
87LA6FU830
Janus Kinases
EC 2.7.10.2
Cyclic Nucleotide Phosphodiesterases, Type 4
EC 3.1.4.17
Imiquimod
P1QW714R7M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
635018Informations de copyright
Copyright © 2021 Zhou, Vadakekolathu, Watad, Sharif, Russell, Rowe, Khan, Millner, Loughenbury, Rao, Dunsmuir, Timothy, Damiani, Pigatto, Malagoli, Banfi, El-Sherbiny, Bridgewood and McGonagle.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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