Techniques and analytic workflow for spatial transcriptomics and its application to allergy and inflammation.

Spatial profiling, through single-cell gene-level expression data paired with cell localization, offers unprecedented biologic insights within the intact spatial context of cells in healthy and diseased tissue, adding a novel dimension to data interpretation. This review summarizes recent developments in this field, its application to allergy and inflammation, and recent single-cell resolution platforms designed for spatial transcriptomics with a focus on data processing and analyses for efficient biologic interpretation of data. By preserving spatial context, these technologies provide critical insights into tissue architecture and cellular interactions that are unattainable with traditional transcriptomics methods, such as revealing localized inflammatory cell network in atopic dermatitis and T-cell interactions in the lung in chronic obstructive pulmonary disease.

Keratin 16 spatially inhibits type I interferon responses in stressed skin.

The stress-induced keratin intermediate filament gene/protein (K16) is spatially restricted to the suprabasal compartment of the epidermis and extensively used as a biomarker for psoriasis, hidradenitis suppurativa, atopic dermatitis and other inflammatory disorders. However, its role in these conditions remains poorly defined. Here we show that K16 negatively regulates type-I interferon (IFN) signaling and innate immune responses.

FABIO: TWAS fine-mapping to prioritize causal genes for binary traits.

Transcriptome-wide association studies (TWAS) have emerged as a powerful tool for identifying gene-trait associations by integrating gene expression mapping studies with genome-wide association studies (GWAS). While most existing TWAS approaches focus on marginal analyses through examining one gene at a time, recent developments in TWAS fine-mapping methods enable the joint modeling of multiple genes to refine the identification of potentially causal ones. However, these fine-mapping methods have primarily focused on modeling quantitative traits and examining local genomic regions, leading to potentially suboptimal performance.

Rapid response of lichen planus to baricitinib associated with suppression of cytotoxic CXCL13+CD8+ T cells.

BACKGROUNDCutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of IFN-γ, a cytokine implicated in the pathogenesis of LP.METHODSIn this phase II trial, 12 patients with cutaneous LP received 2 mg daily baricitinib for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre- and posttreatment samples.

The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters.

Profiling Long Noncoding RNA in Psoriatic Skin Using Single-Cell RNA Sequencing.

The expressions of long noncoding RNAs (lncRNAs) and their roles in epidermal differentiation have been previously defined using bulk RNA sequencing. Despite their tissue-specific expression profiles, most lncRNAs are not well-annotated at the single-cell level. In this study, we evaluated the use of single-cell RNA sequencing to profile and characterize lncRNAs using data from 6 patients with psoriasis with paired uninvolved and lesional psoriatic skin.

Hyperscanning shows friends explore and strangers converge in conversation.

During conversation, people often endeavor to convey information in an understandable way (finding common ground) while also sharing novel or surprising information (exploring new ground). Here, we test how friends and strangers balance these two strategies to connect with each other. Using fMRI hyperscanning, we measure a preference for common ground as convergence over time and exploring new ground as divergence over time by tracking dyads' neural and linguistic trajectories over the course of semi-structured intimacy-building conversations.

Liquid Biopsy for Proliferative Diabetic Retinopathy: Single-Cell Transcriptomics of Human Vitreous Reveals Inflammatory T-Cell Signature.

Purpose: Current therapies for proliferative diabetic retinopathy (PDR) do not specifically target VEGF-independent, cell-type-specific processes that lead to vision loss, such as inflammatory pathways. This study aimed to identify targetable cell types and corresponding signaling pathways by elucidating the single-cell landscape of the vitreous of patients with PDR.

Design: Case series.

Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling.

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease.

Multi-ancestry Genome-Wide Association Meta-Analysis Identifies Novel Loci in Atopic Dermatitis.

Atopic dermatitis (AD) is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to AD genetic association studies are poised to boost power to detect genetic signal and identify ancestry-specific loci contributing to AD risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve AD cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls.

Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells.

Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells.

Diabetic Wound Keratinocytes Induce Macrophage JMJD3-Mediated Nlrp3 Expression via IL-1R Signaling.

Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns.

tauFisher predicts circadian time from a single sample of bulk and single-cell pseudobulk transcriptomic data.

As the circadian clock regulates fundamental biological processes, disrupted clocks are often observed in patients and diseased tissues. Determining the circadian time of the patient or the tissue of focus is essential in circadian medicine and research. Here we present tauFisher, a computational pipeline that accurately predicts circadian time from a single transcriptomic sample by finding correlations between rhythmic genes within the sample.

Suppression of TCF4 promotes a ZC3H12A-mediated self-sustaining inflammatory feedback cycle involving IL-17RA/IL-17RE epidermal signaling.

IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α stimulation) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner, thus creating a feedback loop.

Lupus dermal fibroblasts are proinflammatory and exhibit a profibrotic phenotype in scarring skin disease.

Fibroblasts are stromal cells known to regulate local immune responses important for wound healing and scar formation; however, the cellular mechanisms driving damage and scarring in patients with cutaneous lupus erythematosus (CLE) remain poorly understood. Dermal fibroblasts in patients with systemic lupus erythematosus (SLE) experience increased cytokine signaling in vivo, but the effect of inflammatory mediators on fibroblast responses in nonscarring versus scarring CLE subtypes is unclear. Here, we examined responses to cytokines in dermal fibroblasts from nonlesional skin of 22 patients with SLE and CLE and 34 individuals acting as healthy controls.

HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling.

Interferon (IFN) activity exhibits a gender bias in human skin, skewed toward females. We show that HERC6, an IFN-induced E3 ubiquitin ligase, is induced in human keratinocytes through the epidermal type I IFN; IFN-κ. HERC6 knockdown in human keratinocytes results in enhanced induction of interferon-stimulated genes (ISGs) upon treatment with a double-stranded (ds) DNA STING activator cGAMP but not in response to the RNA-sensing TLR3 agonist.

Significance of stress keratin expression in normal and diseased epithelia.

A group of keratin intermediate filament genes, the type II and type I and , are deemed stress responsive as they are induced in keratinocytes of surface epithelia in response to environmental stressors, in skin disorders (e.g., psoriasis) and in carcinomas.