Abstract

<strong>Background:</strong> 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. <strong>Methods:</strong> 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. <strong>Results:</strong> We report that the CD1c+ DCs pool from patients with non-infectious uveitis is skewed towards 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. <strong>Conclusions:</strong> These results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. <strong>Funding:</strong> The presented work is supported by UitZicht (project number #2014-4, #2019-10, an #2021-4). The funders had no role in the design, execution, interpretation, or writing of the study.

Data availability

All raw data and data scripts are available via dataverseNL: https://doi.org/10.34894/9Q0FVO and deposited in NCBI's Gene Expression Omnibus accessible through GEO Series accession numbers GSE195501 and GSE194060.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Sanne Hiddingh

    Ophthalmo-Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  2. Aridaman Pandit

    Center for Translational Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2057-9737
  3. Fleurieke Verhagen

    Ophthalmo-Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  4. Rianne Rijken

    Center for Translational Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  5. Nila Hendrika Servaas

    Center for Translational Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9825-7554
  6. Rina CGK Wichers

    Center for Translational Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  7. Ninette H ten Dam-van Loon

    Department of Ophthalmology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  8. Saskia S Imhof

    Ophthalmo-Immunology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  9. Timothy RDJ Radstake

    Department of Ophthalmology, Utrecht University, Utrecht, Netherlands
    Competing interests
    Timothy RDJ Radstake, was a principal investigator in the immune catalyst program of GlaxoSmithKline, which was an independent research program. He did not receive any financial support. Currently, TR is an employee of Abbvie where he holds stock. TR had no part in the design and interpretation of the study results after he started at Abbvie..
  10. Joke H de Boer

    Department of Ophthalmology, Utrecht University, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  11. Jonas JW Kuiper

    Center for Translational Immunology, Utrecht University, Utrecht, Netherlands
    For correspondence
    j.j.w.kuiper@umcutrecht.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5370-6395

Funding

UitZicht (#2014-4)

  • Jonas JW Kuiper

UitZicht (#2019-10)

  • Jonas JW Kuiper

UitZicht (#2021-4)

  • Jonas JW Kuiper

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was conducted in compliance with the Helsinki principles. Ethical approval was requested and obtained from the Medical Ethical Research Committee in Utrecht. All patients signed written informed consent before participation. (METC protocol number #14-065/M).

Copyright

© 2023, Hiddingh et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 877
    views
  • 106
    downloads
  • 7
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Sanne Hiddingh
  2. Aridaman Pandit
  3. Fleurieke Verhagen
  4. Rianne Rijken
  5. Nila Hendrika Servaas
  6. Rina CGK Wichers
  7. Ninette H ten Dam-van Loon
  8. Saskia S Imhof
  9. Timothy RDJ Radstake
  10. Joke H de Boer
  11. Jonas JW Kuiper
(2023)
Transcriptome network analysis implicates CX3CR1-positive type 3 dendritic cells in non-infectious uveitis
eLife 12:e74913.
https://doi.org/10.7554/eLife.74913

Share this article

https://doi.org/10.7554/eLife.74913

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Ainhoa Arbués, Sarah Schmidiger ... Damien Portevin
    Research Article

    The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.

    1. Immunology and Inflammation
    2. Medicine
    Haiyi Fei, Xiaowen Lu ... Lingling Jiang
    Research Article

    Preeclampsia (PE), a major cause of maternal and perinatal mortality with highly heterogeneous causes and symptoms, is usually complicated by gestational diabetes mellitus (GDM). However, a comprehensive understanding of the immune microenvironment in the placenta of PE and the differences between PE and GDM is still lacking. In this study, cytometry by time of flight indicated that the frequencies of memory-like Th17 cells (CD45RACCR7+IL-17A+CD4+), memory-like CD8+ T cells (CD38+CXCR3CCR7+HeliosCD127CD8+) and pro-inflam Macs (CD206CD163CD38midCD107alowCD86midHLA-DRmidCD14+) were increased, while the frequencies of anti-inflam Macs (CD206+CD163CD86midCD33+HLA-DR+CD14+) and granulocyte myeloid-derived suppressor cells (gMDSCs, CD11b+CD15hiHLA-DRlow) were decreased in the placenta of PE compared with that of normal pregnancy (NP), but not in that of GDM or GDM&PE. The pro-inflam Macs were positively correlated with memory-like Th17 cells and memory-like CD8+ T cells but negatively correlated with gMDSCs. Single-cell RNA sequencing revealed that transferring the F4/80+CD206 pro-inflam Macs with a Folr2+Ccl7+Ccl8+C1qa+C1qb+C1qc+ phenotype from the uterus of PE mice to normal pregnant mice induced the production of memory-like IL-17a+Rora+Il1r1+TNF+Cxcr6+S100a4+CD44+ Th17 cells via IGF1–IGF1R, which contributed to the development and recurrence of PE. Pro-inflam Macs also induced the production of memory-like CD8+ T cells but inhibited the production of Ly6g+S100a8+S100a9+Retnlg+Wfdc21+ gMDSCs at the maternal–fetal interface, leading to PE-like symptoms in mice. In conclusion, this study revealed the PE-specific immune cell network, which was regulated by pro-inflam Macs, providing new ideas about the pathogenesis of PE.