Transcriptome network analysis implicates CX3CR1-positive type 3 dendritic cells in non-infectious uveitis
Sanne Hiddingh,
Aridaman Pandit,
Fleurieke Verhagen,
Rianne Rijken,
Nila Hendrika Servaas,
Rina CGK Wichers,
Ninette H ten Dam-van Loon,
Saskia M Imhof,
Timothy RDJ Radstake,
Joke H de Boer,
Jonas JW Kuiper
Affiliations
Sanne Hiddingh
Ophthalmo-Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Fleurieke Verhagen
Ophthalmo-Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Rianne Rijken
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Rina CGK Wichers
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Ninette H ten Dam-van Loon
Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Saskia M Imhof
Ophthalmo-Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Timothy RDJ Radstake
University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands
Joke H de Boer
Ophthalmo-Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Ophthalmo-Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands; Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
Background: Type I interferons (IFNs) promote the expansion of subsets of CD1c+ conventional dendritic cells (CD1c+ DCs), but the molecular basis of CD1c+ DCs involvement in conditions not associated without elevated type I IFNs remains unclear. Methods: We analyzed CD1c+ DCs from two cohorts of non-infectious uveitis patients and healthy donors using RNA-sequencing followed by high-dimensional flow cytometry to characterize the CD1c+ DC populations. Results: We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed toward a gene module with the chemokine receptor CX3CR1 as the key hub gene. We confirmed these results in an independent case–control cohort and show that the disease-associated gene module is not mediated by type I IFNs. An analysis of peripheral blood using flow cytometry revealed that CX3CR1+ DC3s were diminished, whereas CX3CR1− DC3s were not. Stimulated CX3CR1+ DC3s secrete high levels of inflammatory cytokines, including TNF-alpha, and CX3CR1+ DC3 like cells can be detected in inflamed eyes of patients. Conclusions: These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. Funding: The presented work is supported by UitZicht (project number #2014-4, #2019-10, and #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.
