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JCI Insight. 2018 Dec 6;3(23). pii: 95228. doi: 10.1172/jci.insight.95228. [Epub ahead of print]

Enriched Cd141+ DCs in the joint are transcriptionally distinct, activated, and contribute to joint pathogenesis.

Author information

1
Molecular Rheumatology, School of Medicine, Trinity College Dublin, Ireland.
2
Immunology and.
3
Discovery Sciences, Janssen Research & Development, Spring House, Pennsylvania, USA.
4
School of Biochemistry and Immunology, Trinity College Dublin, Ireland.
5
Centre for Arthritis & Rheumatic Diseases, St. Vincent's University Hospital, University College Dublin, Ireland.
6
Department of Rheumatology, Adelaide and Meath Hospital, Dublin, Ireland.
7
Translational Immunology, Schools of Biochemistry and Immunology and Medicine, Trinity College Dublin, Ireland.

Abstract

CD141+ DC are implicated in antiviral and antitumor immunity. However, mechanistic studies in autoimmune disease are limited. This is the first study to our knowledge examining CD141+ DC in autoimmune disease, specifically inflammatory arthritis (IA). We identified significant enrichment of CD141+ DC in the inflamed synovial joint, which were transcriptionally distinct from IA and healthy control (HC) blood CD141+ DC and significantly more activated, and they exhibited increased responsiveness to TLR3. Synovial CD141+ DC represent a bone fide CD141+ DC population that is distinct from CD1c+ DC. Synovial CD141+ DC induced higher levels of CD4+ and CD8+ T cell activation compared with their peripheral blood counterparts, as made evident by expression of IFN-γ, TNF-α, and granulocyte-macrophage CSF (GMCSF). Autologous synovial CD141+ DC cocultures also induce higher levels of these cytokines, further highlighting their contribution to synovial inflammation. Synovial CD141+ DC-T cell interactions had the ability to further activate synovial fibroblasts, inducing adhesive and invasive pathogenic mechanisms. Furthermore, we identify a mechanism in which synovial CD141+ DC are activated, via ligation of the hypoxia-inducible immune-amplification receptor TREM-1, which increased synovial CD141+ DC activation, migratory capacity, and proinflammatory cytokines. Thus, synovial CD141+ DC display unique mechanistic and transcriptomic signatures, which are distinguishable from blood CD141+ DC and can contribute to synovial joint inflammation.

KEYWORDS:

Autoimmunity; Dendritic cells; Immunology

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