Abstract:Abundant heterogeneous immune cells infiltrate lesions in chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-promoting from bystander immune cells. Here, we investigate the landscape of non-communicable inflammatory skin diseases (ncISD) by spatial transcriptomics resulting in a large repository of 62,000 spatially defined human cutaneous transcriptomes from 31 patients. Despite the expected immune cell infiltration, we observe rather low numbers of pathogenic di… Show more
“…Interestingly, we found that IL-17 receptor gene ( IL17RA ) and TNF receptor gene ( TNFRSF1A ) were highly expressed in the epidermis of the PP samples (Fig. 5e ), consistent with the localized cytokine responses identified in keratinocytes 36 . Fig.…”
The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2+ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2+ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2+ myeloid cells, CCR7+LAMP3+ dendritic cells, and CXCR4 expressed on both CD8+ Tc17 cells and keratinocytes, respectively. The SFRP2+ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.
“…Interestingly, we found that IL-17 receptor gene ( IL17RA ) and TNF receptor gene ( TNFRSF1A ) were highly expressed in the epidermis of the PP samples (Fig. 5e ), consistent with the localized cytokine responses identified in keratinocytes 36 . Fig.…”
The immunopathogenesis of psoriasis, a common chronic inflammatory disease of the skin, is incompletely understood. Here we demonstrate, using a combination of single cell and spatial RNA sequencing, IL-36 dependent amplification of IL-17A and TNF inflammatory responses in the absence of neutrophil proteases, which primarily occur within the supraspinous layer of the psoriatic epidermis. We further show that a subset of SFRP2+ fibroblasts in psoriasis contribute to amplification of the immune network through transition to a pro-inflammatory state. The SFRP2+ fibroblast communication network involves production of CCL13, CCL19 and CXCL12, connected by ligand-receptor interactions to other spatially proximate cell types: CCR2+ myeloid cells, CCR7+LAMP3+ dendritic cells, and CXCR4 expressed on both CD8+ Tc17 cells and keratinocytes, respectively. The SFRP2+ fibroblasts also express cathepsin S, further amplifying inflammatory responses by activating IL-36G in keratinocytes. These data provide an in-depth view of psoriasis pathogenesis, which expands our understanding of the critical cellular participants to include inflammatory fibroblasts and their cellular interactions.
“…We next identified all keratinocyte regions immediately adjacent to regions of lymphocytic infiltrate. A published spatial IL-17–induced keratinocyte signature ( 24 ) was quantified in these regions, which revealed activation specifically adjacent to the infiltrate that dampened with increasing spatial distance (Fig. 5B and data file S7).…”
Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.
“…These cytokine positive spots were associated with sets of immune-related genes associated with pathways such as oxidative stress, neutrophil migration (IL17A, IL17F, IL26), apoptosis (IFNG) and type 2 immunity (IL13, IL4). 30 Numerous studies have been conducted to decipher multiple inflammatory pathways leading to psoriasis. Ding et al utilised ST to identify pathways underlying neutrophilic cell death and neutrophil extracellular traps (NETs), which consist of enzyme and peptides aggregating dead neutrophils.…”
Section: Inflammatory Diseasesmentioning
confidence: 99%
“…Non‐communicable inflammatory diseases (nISD) are diseases classified by altered adaptive immune responses, mostly based on lymphocyte interaction 30 . A recent study, aiming to investigate the inflammatory responder genes underlying adaptive immune responses has applied ST in lesional and non‐lesional skin from patients with psoriasis, atopic dermatitis and lichen planus (LP).…”
Section: Applications In Skin Researchmentioning
confidence: 99%
“…Other disease‐driving cytokines such as IL17F, IL21, IL22, TNF, IL4 were found in psoriasis and atopic dermatitis. These cytokine positive spots were associated with sets of immune‐related genes associated with pathways such as oxidative stress, neutrophil migration (IL17A, IL17F, IL26), apoptosis (IFNG) and type 2 immunity (IL13, IL4) 30 …”
Tissues and organs of multicellular organisms are spatially organised by the compartmentalisation of cell types and subpopulations that are coordinated in internal gene regulatory networks, and by signalling from their surrounding tissue environment. In order to perform a subset of biologic processes, these cells differ in terms of localisation, morphology and gene expression patterns. 1 The development of single-cell methods has enabled studies that can retain cellular properties and heterogeneity at a single-cell resolution, which has led to a more detailed understanding of physiologic and disease conditions. 2 One of the most popular methods, single-cell RNA-sequencing (scRNA-seq), has made it possible to profile the whole transcriptome of each individual cell. 3,4 However, it results in the loss of information on spatial relationships among the cell populations since it entails dismantling of the original tissue into single-cell suspensions through mechanical and enzymatic dissociation steps, which could perturb or alter the cell's gene expression. 5 Recently, various techniques have been developed aiming for transcriptome mapping while preserving the spatial location of the expressed transcripts within intact tissues. 6 These methods, collectively known as spatial transcriptomics (ST), have been voted as the method of the year 2020 by Nature Methods and expect to provide remarkable novel insights in the
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