| Autor: |
Sanne Hiddingh, R. Komer-Wichers, S. S. Imhof, Trdj Radstake, Fleurieke H. Verhagen, Rianne Rijken, Aridaman Pandit, Johan Kuiper, Nila H. Servaas, N. t. Dam-van Loon, J H de Boer |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
BackgroundInflammatory subsets of CD1c+ conventional dendritic cells (CD1c+ DCs) are promoted by type I interferons (IFN), but the molecular basis for CD1c+ DCs involvement in conditions not driven by type I IFNs is unknown. MethodsOur objective was to use RNA-sequencing of blood CD1c+ DCs and high-dimensional flow cytometry of two cohorts of autoimmune uveitis patients and healthy donors to characterize the CD1c+ DCs population of type I IFN-negative autoimmune uveitis. ResultsWe report that the CD1c+ DCs pool from patients with autoimmune uveitis (n=45) is skewed towards a transcriptional network characterized by surface receptor genes CX3CR1, CCR2, and CD36. We confirmed the association of the transcriptional network with autoimmune uveitis by RNA-sequencing in another case-control cohort (n=35) and demonstrated that this network was governed by NOTCH2-RUNX3 signaling. Unbiased flow cytometry analysis based on the transcriptional network identified blood CD1c+ DC subsets that can be distinguished by CX3CR1 and CD36 surface expression. A CD36+CX3CR1+CD1c+ DC subset within the novel DC3 population was diminished in peripheral blood of patients, while CD1c+ DCs expressing CD36 and CX3CR1 accumulate locally in the inflamed eye. The CD36+CX3CR1+CD1c+ DC subset showed a differential capacity to produce cytokines, including TNF-alpha, IL-6, and VEGF, but not IL-23. ConclusionThese results show that CD1c+ DC subsets defined on the basis of surface expression of CD36 and CX3CR1 are linked to type I IFN-negative human autoimmune uveitis and show a differential capacity to secrete proinflammatory mediators that drive its pathophysiology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/468816v1_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@14f8f2borg.highwire.dtl.DTLVardef@406a5eorg.highwire.dtl.DTLVardef@1075804org.highwire.dtl.DTLVardef@1238bdc_HPS_FORMAT_FIGEXP M_FIG C_FIG |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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