Inflammatory diseases encompass a wide range of conditions characterized by chronic inflammation, such as rheumatoid arthritis, inflammatory bowel disease, and asthma. Understanding the intricate mechanisms underlying these diseases is crucial for developing targeted therapies. This is where single-cell RNA sequencing (scRNA-seq) data is a game-changer for researchers. By analyzing gene expression profiles at the individual cell level, scRNA-seq unveils the remarkable heterogeneity of cell types involved in inflammation. With scRNA-seq, researchers can decipher the intricate orchestration of the inflammatory response, identifying key genes, pathways, and potential therapeutic targets.

"scRNA-seq illuminates the hidden symphony of inflammation, revealing the molecular players that dance to the tune of disease progression."

The ‘Monthly Dataset Roundup’ series features datasets on Polly that are of scientific value, intended to promote data sharing and reuse of multi-omics data. This month, we are featuring datasets that capture the comprehensive molecular landscape of inflammatory diseases, curated versions of which can be found and analyzed on Polly.

Dataset 1

Skin single-cell universe identifies IL-1B/IL23A co-producing CD14+ type 3 dendritic cells in psoriasis.

Dataset ID: GSE176509_GPL20301
Year of Publication: 2022
Total Samples: 1486
Experiment type: Expression profiling by high throughput sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis (PSO), are underpinned by dendritic cell- (DC) mediated T-cell responses. The heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. In this study, index-sorted single-cell flow cytometry and RNA-sequencing of lesional and non-lesional AD and PSO skin was performed to identify macrophages and all DC subsets, including the newly-described mature LAMP3+BIRC3+ DC enriched in immunoregulatory molecules (mregDC) and DC3.

The authors generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin by integrating the indexed data with published skin datasets. Importantly, they found that CD14+ DC3 were increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathologic in PSO. The study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution and identifies CD14+ DC3 as potential promotors of inflammation in PSO.

‍Dataset 2

Intra- and inter-cellular rewiring of the human colon during ulcerative colitis

Dataset ID: SCP259_1
Year of Publication: 2019
No. of cells: 366,650
Experiment type: Genome-wide association studies
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, this study generated an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which the authors associate with resistance to anti-TNF treatment.

Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type-specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, the authors nominated and inferred functions for specific risk genes across GWAS loci. This work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.

Noteworthy Single-cell RNA-seq Datasets on Inflammatory Diseases

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Dataset 3

Single-cell RNA-seq of psoriatic skin identifies pathogenic Tc17 subsets and reveals distinctions between CD8+ T cells in autoimmunity and cancer.

Dataset ID: GSE146264_GPL20301
Year of Publication: 2021
Total Samples: 6663
Experiment type: Single-cell RNA-seq
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Psoriasis is an inflammatory, IL-17-driven skin disease in which autoantigen-induced CD8+ T cells have been identified as pathogenic drivers. This study used single-cell RNA-seq to identify 11 transcriptionally diverse CD8+ T cell subsets in psoriatic and healthy skin. Among several inflammatory subsets enriched in psoriatic skin, the authors observed two Tc17 subsets that were metabolically divergent, developmentally related, and expressed CXCL13, which we found to be a biomarker of psoriasis severity.

Despite high co-inhibitory receptor expression in the Tc17 clusters, a comparison of these cells with melanoma-infiltrating CD8+ T cells revealed upregulated cytokine, cytolytic, and metabolic transcriptional activity in the psoriatic cells that differed from an exhaustion program. The findings provide a high-resolution view of cutaneous CD8+ T cells in psoriasis and healthy skin and shed light on their functional distinctions within the chronic pathologies of autoimmunity and cancer.

Dataset 4

CSF B cells in relapsing multiple sclerosis are driven towards an antigen-experienced, inflammatory fate.

Dataset ID: GSE133028_GPL20301
Year of Publication: 2020
Total Samples: 55
Experiment type: Expression profiling by high throughput sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3).

Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence-activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells.

Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While the authors identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. The findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

Dataset 5

Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease

Dataset ID: E-HCAD-11
Year of Publication: 2021
No. of cells: 21,664
Experiment type: Expression profiling by high throughput sequencing
Organism: Homo sapiens
Reference link: Raw data

Summary:
Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts.

We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.

Polly’s OmixAtlases provide FAIR biomolecular data on the Polly platform, enabling researchers to conduct robust data analysis and effectively consume omics data. Email us at info@elucidata.io for more information.

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