ObjectiveBacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.MethodsNormal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFN alpha production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFN alpha protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.ResultsCD45+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 IFN alpha and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFN alpha 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-kappa B signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFN alpha. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 +/- 4 pre-infection and 35.3 +/- 7.5 during infection).ConclusionEntheseal pDCs link microbes to TNF/IFN alpha 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.

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

Banfi, Giuseppe;
2021

Abstract

ObjectiveBacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.MethodsNormal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFN alpha production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFN alpha protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.ResultsCD45+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 IFN alpha and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFN alpha 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-kappa B signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFN alpha. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 +/- 4 pre-infection and 35.3 +/- 7.5 during infection).ConclusionEntheseal pDCs link microbes to TNF/IFN alpha 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.
COVID-19
enthesis
interferon alpha
plasmacytoid dendritic cells
psoriatic arthritis
Adjuvants, Immunologic
Adult
Aged
Arthritis, Psoriatic
COVID-19
Computational Biology
Cyclic Nucleotide Phosphodiesterases, Type 4
Dendritic Cells
Female
Gene Expression Regulation
Humans
Imiquimod
Interferon-alpha
Janus Kinases
Male
Middle Aged
NF-kappa B
Oligonucleotides
Phosphodiesterase 4 Inhibitors
Piperidines
Protein Kinase Inhibitors
Pyrimidines
Signal Transduction
Toll-Like Receptor 7
Toll-Like Receptor 9
Transcriptome
Tumor Necrosis Factor-alpha
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/132093
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