Biology subjects

Radstake, T.

Publications and source records attributed to Radstake, T..

4 recordsLinked to original sources

bioRxiv2024

Single-cell Landscape of Immune Cells in Blood and Skin in Psoriasis

BackgroundPsoriasis is a systemic inflammatory disease for which there is currently no cure, in part due to an incomplete understanding of its pathophysiology. MethodsTo better understand the immune response in psoriasis, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) and on lesional and non-lesional skin samples from a cohort of 11 psoriasis patients and 8 healthy controls. Additionally, we conducted flow cytometry on PBMCs from a separate cohort of 13 psoriasis patients and 11 ankylosing spondylitis. FindingsOur study revealed altered immune signatures of specific myeloid and lymphocyte subsets in blood and skin, both in terms of cell numbers and gene expression. Specifically, we discovered elevated proportions of circulating CD14++ monocytes, increased expression of major histocompatibility complex (MHC) class II molecule by circulating CD16+ monocytes, as well as increased expression of genes related to skin homing and to pro-inflammatory responses in psoriasis by circulating plasmacytoid dendritic cells (pDCs). Circulating CD8+ T effector memory cells in psoriasis patients exhibited reduced abundance but increased skin-homing potential. In psoriatic lesions, we observed a hyperinflammatory myeloid-cell state and enrichment of IL17-producing cells with a tissue-resident memory T-cell signature. InterpretationThe changes in immune cell numbers and gene expression indicate a significant alteration in the immune landscape of psoriasis patients. This suggests that the immune system in psoriasis is reprogrammed, affecting both innate and adaptive branches. These findings provide new insights into the aberrant immune-cell signatures in the circulation and skin lesions in psoriasis, and thereby help to understand its pathophysiology. FundingThis study was financially supported by the National Natural Science Foundation of China (U23A6012), Science and Technology Planning Project of Guangzhou (2024A03J0055, 202206080005), Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202204).

systems biology↗

bioRxiv2021

Interactions of host defense and hyper-keratinization in psoriasis

ObjectivesTo understand the crosstalk between the host and microbiota in psoriatic skin, using a systems biology approach based on transcriptomics and microbiome profiling. MethodsWe collected the skin tissue biopsies and swabs in both lesion and non-lesion skin of 13 patients with psoriasis (PsO), 15 patients with psoriatic arthritis (PsA), and healthy skin from 12 patients with ankylosing spondylitis (AS). We performed transcriptome sequencing and metagenomics profiling on the local skin sites to study the similarities and differences in the molecular profiles between the three conditions, and the associations between the host defense and microbiota dynamic. ResultsWe found that lesion and non-lesional samples were remarkably different in terms of their transcriptome profiles. Functional annotation of differentially expressed genes (DEGs) showed a major enrichment in neutrophil activation. By using coexpression gene networks, we identified a gene module that was associated with local psoriasis severity at the site of biopsy. From this module, we extracted a "core" set of genes that were functionally involved in neutrophil activation, epidermal cell differentiation and response to bacteria. Skin microbiome analysis revealed that the abundance of Enhydrobacter, Micrococcus and Leptotrichia were significantly correlated with the "core network" of genes. ConclusionsWe identified a core network that regulates inflammation and hyper-keratinization in psoriatic skin, and is associated with local disease severity and microbiome composition.

systems biology↗

bioRxiv2021

Whole transcriptome-sequencing and network analysis of CD1c+ human dendritic cells identifies cytokine-secreting subsets linked to type I IFN-negative autoimmunity to the eye

BackgroundType 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. MethodsWe 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. ResultsWe 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. ConclusionsThese results show that CX3CR1+ DC3s are implicated in non-infectious uveitis and can secrete proinflammatory mediators implicated in its pathophysiology. FundingThe 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.

immunology↗

bioRxiv2020

Inhibitory CD200-receptor signaling is rewired by type I interferon

CD200 Receptor 1 (CD200R) is an established inhibitory immune receptor that inhibits TLR-induced cytokine production through Dok2 and RasGAP. RasGAP can be cleaved under certain conditions of mild cellular stress. We found that in the presence of cleaved RasGAP, CD200R loses its capacity to inhibit rpS6 phosphorylation. Furthermore, IFN pre-stimulation of human mononuclear cells results in increased amounts of cleaved RasGAP. Coherently, upon pretreatment with increasing concentrations of IFN, CD200R gradually shifts from an inhibitor to a potentiator of TLR7/8-induced IFNG mRNA production. In peripheral blood mononuclear cells from Systemic Lupus Erythematosus (SLE) patients, a prototypic type I IFN disease, we found an increased proportion of cleaved RasGAP compared to healthy controls. In line with this, in subsets of SLE patients the inhibitory function of CD200R is lost or converted to a potentiating signal for IFNG mRNA production. Thus, our data show that type I IFN rewires CD200R signaling and suggest that this cell-extrinsic regulation of signaling could contribute to perpetuation of inflammation in SLE.

immunology↗