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

Zhou, Q., Vadakekolathu, J., Watad, A., Sharif, K., Russell, T., Rowe, H., Khan, A., Millner, P.A., Loughenbury, P., Rao, A., Dunsmuir, R., Timothy, J., Damiani, G., Pigatto, P.D.M., Malagoli, P., Banfi, G., El-Sherbiny, Y.M. ORCID: 0000-0003-4791-3475, Bridgewood, C. and McGonagle, D., 2021. 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. Frontiers in Immunology, 12: 635018. ISSN 1664-3224

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Abstract

Objective: Bacterial 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Item Type: Journal article
Publication Title: Frontiers in Immunology
Creators: Zhou, Q., Vadakekolathu, J., Watad, A., Sharif, K., Russell, T., Rowe, H., Khan, A., Millner, P.A., Loughenbury, P., Rao, A., Dunsmuir, R., Timothy, J., Damiani, G., Pigatto, P.D.M., Malagoli, P., Banfi, G., El-Sherbiny, Y.M., Bridgewood, C. and McGonagle, D.
Publisher: Frontiers Media
Date: 15 April 2021
Volume: 12
ISSN: 1664-3224
Identifiers:
NumberType
10.3389/fimmu.2021.635018DOI
1443906Other
Rights: © 2021 Zhou, Vadakekolathu, Watad, Sharif, Russell, Rowe, Khan, Millner, Loughenbury, Rao, Dunsmuir, Timothy, Damiani, Pigatto, Malagoli, Banfi, El-Sherbiny, Bridgewood and McGonagle. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Divisions: Schools > School of Science and Technology
Record created by: Jonathan Gallacher
Date Added: 07 Jun 2021 14:20
Last Modified: 07 Jun 2021 14:20
URI: http://irep.ntu.ac.uk/id/eprint/43008

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