Biology subjects

Bogle, R.

Publications and source records attributed to Bogle, R..

7 recordsLinked to original sources

bioRxiv2026

Disease-specific differences in particulate matter handling drive pathogenic responses in human derived nasal epithelial cells

BackgroundParticulate matter (PM) exposure is associated with increased risk and exacerbation of chronic rhinosinusitis (CRS), yet underlying mechanisms remain poorly understood. ObjectiveTo define the epithelial mechanisms by which PM exposure promotes and exacerbates CRS, with a focus on epithelial remodeling, inflammation, barrier dysfunction, and cellular uptake of PM. MethodsHuman nasal epithelial cells obtained from ethmoid tissue of CRS (n = 5) and control donors (n = 4) were cultured at an air-liquid interface and exposed to PM. Single-cell RNA sequencing was performed to characterize PM-induced cellular and transcriptional changes. Protein expression, epithelial barrier integrity, cell death, and intracellular PM uptake were evaluated using biochemical, imaging, and ultrastructural approaches. ResultsUnsupervised clustering identified seven epithelial cell populations. Gene set analysis revealed baseline enrichment of inflammatory and keratinization pathways and reduced ciliogenesis in CRS compared with controls. Although PM induced inflammation and squamous differentiation in controls, the pathogenic responses were significantly amplified in CRS, including uniquely enhanced IL-1 signaling. Transcriptional changes were validated by ELISA, transepithelial electrical resistance, and immunofluorescence, demonstrating increased inflammation, epithelial barrier disruption, and cell death following PM exposure. Transmission electron microscopy revealed increased intracellular PM within membrane-bound organelles. Pre-treatment with an endocytosis inhibitor rescued PM-induced epithelial barrier dysfunction and inflammation. ConclusionCRS epithelium exhibits baseline dysfunction that may predispose it to environmental injury. PM exposure both induces CRS-like epithelial changes in controls and exacerbates disease-associated phenotypes. Key MessagesO_LICompared to controls, CRS nasal epithelium exhibits baseline inflammatory, keratinization, and ciliogenesis abnormalities. C_LIO_LIParticulate matter induces inflammation and squamous differentiation, while amplifying epithelial injury that is more robust in CRS epithelium compared to controls. C_LIO_LIInhibition of dynamin-dependent endocytosis rescues PM-induced epithelial barrier leakiness and inflammation, implicating intracellular particulate matter uptake in disease pathogenesis. C_LI Capsule SummaryParticulate matter induces CRS-like epithelial remodeling in controls and exacerbates inflammation and epithelial barrier dysfunction in CRS nasal epithelium, which can be rescued with endocytosis inhibition. This suggests a mechanistic link between baseline CRS vulnerability, intracellular uptake of particulate matter, and disease pathogenesis.

cell biology↗

bioRxiv2026

Restoration of Keratinocyte Homeostasis Drives Resolution of Skin Inflammation

Chronic skin inflammation is sustained by reciprocal interactions between epidermal dysfunction and immune activation, yet whether epithelial state actively governs restoration of tissue homeostasis remains unclear. Using a murine model of inflammatory skin disease, we modulated epidermal lipid metabolism and examined its effects on tissue organization. Transcriptomic profiling revealed coordinated reversal of inflammatory, metabolic, and structural gene programs accompanied by normalization of epidermal architecture. Single-cell RNA sequencing showed that this remodeling was concentrated in differentiated keratinocytes, with suppression of IL-17 and neutrophil-associated responses and restoration of barrier and mitochondrial-lipid programs, while stromal and myeloid compartments displayed secondary adaptation. Cross-species analysis demonstrated that resolution-associated gene networks are inversely regulated in human psoriasis. Integrated proteomic and transcriptomic analyses further identified a conserved epithelial regulatory triad whose concordant regulation in psoriasis and atopic dermatitis, and whose in vivo silencing, establish mechanistic control of disease severity. Together, these findings indicate that inflammatory resolution reflects reorganization of epidermal transcriptional networks and position epithelial state as a determinant of inflammatory persistence.

cell biology↗

bioRxiv2025

Cross-disease comparison of dermatomyositis and lupus skin identifies inflammatory monocytes and JAK-1 signaling as drivers of vasculopathy in dermatomyositis

Dermatomyositis (DM) is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. DM and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features, yet disparate responses to available therapeutics. DM skin disease is often relapsing and recalcitrant. To investigate DM immunopathogenesis, non-lesional skin, lesional skin, and circulating immune cells from DM patients were analyzed using single-cell RNA-sequencing. Samples were analyzed in parallel with lesional and non-lesional lupus skin, healthy control skin, and peripheral blood. We demonstrate a pervasive type I interferon (IFN) signature in DM stroma that persists in culture and is distinguished from lupus by upregulation of VEGF and IL-18 signaling in DM keratinocytes. Furthermore, endothelial cells (ECs) in lesional DM exhibit decreased proliferation that was not observed in lupus. Using cell communication networks, we identified a population of DM-specific monocytes interacting with non-proliferating DM ECs. Co-culture of monocytes from DM patients with ECs resulted in increased EC apoptosis inhibited by JAK1 blockade. JAK1 inhibition also resulted in reversal of DM-stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and non-lesional skin of DM compared to lupus and implicate monocyte-mediated EC dysfunction in DM vasculopathy and support JAK inhibition for refractory skin disease.

immunology↗

bioRxiv2025

TWEAK Signaling Drives the Transition from Psoriasis to Atopic Dermatitis-like Inflammation in Paradoxical Skin Reactions

Targeted biologics have significantly advanced the treatment of inflammatory skin diseases such as psoriasis; however, some patients paradoxically develop eczematous skin reactions during or after anti-TNF, IL-17, or IL-23 therapy. Although these paradoxical reactions resemble atopic dermatitis clinically and histologically, the molecular mechanisms that drive their development are not fully understood. Here, we generated high-resolution cellular and spatial maps of healthy skin, psoriasis, atopic dermatitis, and paradoxical reactions using single-cell RNA sequencing, spatial transcriptomics, immunohistochemistry, and in vitro assays. In paradoxical reactions, we identified a distinct transcriptional landscape characterized by myeloid and T-cell expansion and an altered keratinocyte phenotype shaped by TWEAK signaling. Mechanistically, we showed that TWEAK synergizes with IL-13 to drive the Th2/type I interferon-polarized epithelial program. Notably, anti-TNF therapy induced TWEAK gene expression in myeloid cells, suggesting a compensatory inflammatory circuit. Together, these findings identify the TWEAK-IL-13 axis as a central driver of paradoxical skin reactions and provide a mechanistic framework for how cytokine blockade may rewire cutaneous immune responses. One Sentence Summary The TWEAK-IL-13 signaling axis is a key driver of immune reprogramming underlying paradoxical skin reactions.

immunology↗

bioRxiv2025

VGLL3-centered network connects placental, vascular, and immune defects in preeclampsia

Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche. Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription co-regulator in the Hippo pathway, is upregulated in preeclamptic placentas. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction, all of which contribute to pregnancy-related hypertension, fetal growth restriction, and offspring mortality. Our data reveal that VGLL3 acts upstream of preeclampsia-associated processes, including the production of sFLT1, a key biomarker of the disease. Notably, targeting VGLL3--either by genetic deletion in mouse placentas or through therapeutic inhibition in human placentas--protects against preeclampsia and alleviates disease pathology. These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.

immunology↗

bioRxiv2025

A Transcriptomic Atlas of Healthy Human Skin Links Regional Identity to Inflammatory Disease.

Human skin is not a uniform organ but a mosaic of anatomically distinct niches, with each site finely tuned to unique environmental demands and immune pressures. Yet, the molecular determinants that define these regional identities and their relationship to site-specific vulnerability to inflammatory disease remain poorly understood. Here, we generate a high-resolution single-cell atlas of human skin, profiling 274,834 cells from 96 healthy samples across 7 anatomically distinct sites (acral, arm, axilla, back, face, leg and scalp). Our analysis reveals striking region-specific transcriptional and cellular networks, uncovering how local immune-stromal crosstalk governs tissue homeostasis and underpins anatomical susceptibility to distinct inflammatory diseases such as such as systemic lupus erythematosus (SLE), atopic dermatitis (AD), and psoriasis. These findings illuminate the tissue-intrinsic foundations of regional immune identity and provide a blueprint/resource for the development of precision therapies tailored to the distinct immunological microenvironments of specific anatomical skin sites.

systems biology↗

bioRxiv2024

Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet's syndrome

Sweets syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweets syndrome revealed a prominent interferon signature in Sweets syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweets syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweets syndrome through recognition of type I interferons.

immunology↗