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Single Cell and Spatial Sequencing Characterizes Cell Type Composition and Cell-Cell Interaction in Psoriasis

ABSTRACT: The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is still incompletely understood. Here we demonstrate, using a combination of single-cell and spatial-sequencing, that psoriatic fibroblasts, a hitherto unappreciated participant in psoriasis pathogenesis, contribute to the immune network in psoriasis through transition to a pro-inflammatory state characterized by CCL19 and CCL13. Fibroblasts interact with three other main cell-types that are in close proximity: keratinocytes, T cells and myeloid cells, that also interact with each other. In addition, our data demonstrates striking compartmentalization of inflammatory responses in distinct layers of the psoriatic epidermis, including IL-17A responses and autocrine IL-36 autoinflammatory activity within the supraspinous layer. Lastly, our data defined the T cell and myeloid populations involved in psoriasis, including enrichment of CD8+ IL17A expressing T cells, CD16+ dendritic cells, and LAMP3+ dendritic cells. These data provide an unprecedented view of psoriasis pathogenesis, which expands our understanding of the critical cellular players to include inflammatory fibroblasts as well as their cell-cell interactions, defines the spatial compartmentalization of specific inflammatory processes, together a unique resource for future investigations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE173706 | GEO | 2022/09/20

REPOSITORIES: GEO

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Project description:Background: Monocytes and macrophages are implicated in inflammation and atherosclerosis, whereas monocytes are involved in psoriasis lesion formation. We previously reported a psoriatic inflammation-associated significant decrease in the membrane protein caveolin-1 (CAV-1) in psoriasis patient monocytes. However, the phenotype of circulating monocytes and their macrophage differentiation in psoriasis patients remain unclear. Objective: We sought to clarify circulating monocyte and monocyte-derived macrophage (MDM) phenotypes in psoriasis patients with and without comorbidities. Method: Thirty-one patients with psoriasis vulgaris and 28 control subjects were included. Surface macrophage markers and inflammatory status were examined in circulating monocytes and MDMs from both groups. Expression of CD36, which mediates macrophage uptake of oxidized low-density lipoprotein (oxLDL), was evaluated in these cells. CAV-1-silenced monocytes were differentiated into macrophages to investigate the effects of CAV-1 downregulation on psoriatic inflammation and atherosclerosis. Results: Macrophage surface markers were detectable in circulating monocytes. A significant M1 shift was detected in monocytes and MDMs in psoriasis patients, including those without cardiovascular disease risk factors, as compared to controls. MDMs of psoriasis patients had more CD36-expressing cells, which are associated with atherosclerosis risk. Additionally, CAV-1-silencing in monocytes increased the likelihood of M1-biased macrophage differentiation and increased pro-inflammatory cytokine production. Conclusions: Monocytes from psoriasis patients were more likely to differentiate into M1-dominant macrophages, correlating with inflammatory status and CAV-1 expression. These aberrant inflammatory monocytes not only contribute to psoriatic inflammation by producing psoriatic cytokines, but also have a phenotype that could increase atherosclerosis risk by uptake of oxLDL and formation of foam cells.

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Single Cell and Spatial Sequencing Characterizes Cell Type Composition and Cell-Cell Interaction in Psoriasis

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