Single-cell analysis of psoriasis resolution reveals an inflammatory fibroblast state targeted by IL-23 blockade
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Abstract
Biologics targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis. However, the early mechanisms of action of these drugs remain poorly understood. Here, we performed longitudinal single-cell RNA-sequencing in affected individuals receiving IL-23 inhibitor therapy. By profiling skin at baseline, day 3 and day 14 of treatment, we demonstrated that IL-23 blockade causes marked gene expression shifts, with fibroblast and myeloid populations displaying the most extensive changes at day 3. We also identified a transient WNT5A+/IL24+ fibroblast state, which was only detectable in lesional skin. In-silico and in-vitro studies indicated that signals stemming from these WNT5A+/IL24+ fibroblasts upregulated multiple inflammatory genes in keratinocytes. Importantly, the abundance of WNT5A+/IL24+ fibroblasts was significantly reduced after treatment. This observation was validated in-silico , by deconvolution of multiple transcriptomic datasets, and experimentally, by RNA in-situ hybridization. These findings demonstrate that the evolution of inflammatory fibroblast states is a key feature of resolving psoriasis skin.
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ACKR1+/FABP4+ capillaries FDR<10-7 in both)
Missing parenthesis: “ACKR1+/FABP4+ capillaries (FDR<10-7 in both).”
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reduction of WNT5A+/IL24+ fibroblasts as an early eventmediating the resolution of skin inflammation in psoriasis, following systemic or topical treatment
This is an interesting finding! I imagine that it could be helpful to use this as a potential in screen for new psoriasis treatments if human diseased skin is accessible (with the caveat that this finding was based on samples from males of European descent).
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topicalglucocorticoid (halometasone monohydrate 0.05% cream)
It would be nice to see whether the reduction of WNT5A+/IL24+ fibroblasts also occurred for class V-VII corticosteroids given that the the higher potency corticosteroids are advised for short-term use. I wonder if a reduction in the WNT5A+/IL24+ fibroblast cells would occur as quickly or with the same magnitude when using less potent/strong corticosteroid medications. I’d also be interested to see if Vtama (tapinarof) leads to a WNT5A+/IL24+ fibroblast reduction as well.
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