The PAR2/TRPV3/IL-33 Axis in Keratinocytes Drives Neuroimmune
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE297292 | GEO | 2026/01/01
REPOSITORIES: GEO
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Project description:The PAR2/TRPV3/IL-33 Axis in Keratinocytes Drives Neuroimmune
| PRJNA1263468 | ENA
Project description:Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous lesions and intense pruritus. Skin inflammation mediated by transient receptor potential vanillin 3 (TRPV3) in keratinocytes is a key mechanism driving the progression of AD. Paeonol is a bioactive phenolic compound extracted from the root bark of the Paeonia genus, which has demonstrated anti-inflammatory activities. Whether paeonol alleviates skin inflammation by inhibiting TRPV3 in the treatment of AD remains unclear.Objective: This study aims to investigate the therapeutic efficacy of paeonol against AD and its underlying anti-inflammatory mechanism.Methods: The therapeutic effects of paeonol were evaluated in a mouse model of AD induced by MC903 or carvacrol, as well as in tumor necrosis factor-alpha (TNF-α)-stimulated HaCaT cell line. Itch-related behaviors, hematoxylin-eosin (H&E) staining and toluidine blue staining were assessed in AD mice to evaluate the anti-atopic activity of paeonol. TRPV3 expression and function in keratinocytes were examined by Quantitative Real-time-PCR (qPCR), WB, immunofluorescence (IF) and Ca2+ imaging experiments. The anti-inflammation effect and its mechanisms of paeonol were measured by RNA sequencing (RNA-seq), H&E staining, qPCR and ELISA. Whole-cell patch-clamp were used to measure the excitability of trigeminal ganglion (TG) neurons treated by Chemokine (C-C motif) ligand 3 (CCL3).Results: Paeonol significantly alleviated MC903 and carvacrol-induced pruritus, epidermal hyperplasia and skin inflammation. Paeonol inhibited the expression and function of TRPV3 in keratinocytes, thereby inhibiting the activating of nuclear factor κB (NF-κB) pathway and reducing the secretion of CCL3. Downregulation of CCL3 expression in keratinocytes reduces the number of macrophages in the skin and inhibits their polarization to the M1 type. Moreover, paeonol also reversed the hyperexcitability of TG induced by increased CCL3, thus alleviated pruritus. Conclusion: Our study demonstrated that the activation of TRPV3 in keratinocytes aggravated skin inflammation and pruritus by promoting the secretion of CCL3. Paeonol alleviated AD by inhibiting the TRPV3/NF-κB/CCL3 axis in keratinocytes, thereby reducing macrophage-related skin inflammation, and inhibiting the hyperexcitability of TG neurons. These findings provide a novel therapeutic mechanism of paeonol in treating AD.
2025-12-01 | GSE289250 | GEO
Project description:To understand the impact of dysfunctional TRPV3 on keratinocyte proliferation and differentiation, we conducted transcriptomic analysis on cells that express cloned different TRPV3 mutations identified in focal palmoplantar keratoderma (FPPK) patients and identified a number of perturbed pathways associated with epidermal cells construction and development. We also analyzed the molecular changes of skin biopsy samples from patients. Our data suggests that TRPV3 dysfunction inhibits keratinocyte differentiation, actives apoptosis pathway resulted in cell death, and disturbs the balance between keratinocyte proliferation and differentiation processes in the skin.
2015-12-31 | GSE71236 | GEO
Project description:To understand the impact of dysfunctional TRPV3 on keratinocyte proliferation and differentiation, we conducted transcriptomic analysis on cells that express cloned different TRPV3 mutations identified in focal palmoplantar keratoderma (FPPK) patients and identified a number of perturbed pathways associated with epidermal cells construction and development. We also analyzed the molecular changes of skin biopsy samples from patients. Our data suggests that TRPV3 dysfunction inhibits keratinocyte differentiation, actives apoptosis pathway resulted in cell death, and disturbs the balance between keratinocyte proliferation and differentiation processes in the skin. To explore the functional impact of the different TRPV3 mutations on cells, we cloned the wild type and mutant TRPV3 clones into expression vector. The wild-type human TRPV3 gene was amplified from cDNA made from a mixture of human tissue total RNA and cloned into pcDNA3.1 (Life Technologies, Carlsbad, CA). The accuracy of the cloned sequence was checked with Sanger sequencing. Quick Change II XL site-directed mutagenesis kit (Agilent, Santa Clara, CA) was used to introduce sequence changes corresponding to mutations observed in patients. The HEK293T cells were transfected using Lipofectamine 2000 (Life Technologies, Carlsbad, CA) according to the manufacturerâs instructions. Cells were also transfected with the same plasmid without insert as control.
2015-12-31 | E-GEOD-71236 | biostudies-arrayexpress
Project description:TRPV3 is highly expressed in human skin and is involved in the development of inflammatory dermatoses. However, it remains unclear whether TRPV3 influences inflammation in human sebaceous glands and its role in the pathogenesis of acne. Here, we showed that TRPV3 expression was increased in the sebaceous glands of facial acne lesions and acne-like mice. TRPV3 increased the secretion of pro-inflammatory cytokines and chemokines in human SZ95 sebocytes, as well as the chemotaxis of neutrophils, which were the major immune cells found in acne lesions. We demonstrated that P.acnes promoted TRPV3 expression through regulating lipid profile especially upregulated arachidonic acid levels in human sebocytes. TRPV3 further upregulated TLR2 expression by promoting transcriptional factor p-FOSL1 expression and its binding to the TLR2 promoter, leading to downstream NF-κB signaling activation. Importantly, either genetic silencing or pharmacological inhibition of TRPV3 alleviated acne-like inflammation in mice, showing reduced acne-characteristic cytokines and chemokines production and neutrophil infiltration by inhibiting the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebocytes inflammation, which was involved in the development of acne, indicating that TRPV3 is a potential therapeutic target for acne and other disorders of the pilosebaceous unit.
2023-10-13 | GSE245001 | GEO
Project description:We identified a number of affected pathways through transcriptome analysis on the skin biopsy samples of the FPPK patients. Our findings suggest that TRPV3 dysfunction may increase apoptotic activity, inhibit keratinocyte differentiation and disturb the intricate balance between proliferation and differentiation state of keratinocytes in the skin. To understand the effect of TRPV3 mutation, transcriptome of HaCaT cell lines transfected with mutant TRPV3 were profiled in time-course manner (16, 24 and 40hr).
2013-12-24 | E-GEOD-53615 | biostudies-arrayexpress
Project description:We identified a number of affected pathways through transcriptome analysis on the skin biopsy samples of the FPPK patients. Our findings suggest that TRPV3 dysfunction may increase apoptotic activity, inhibit keratinocyte differentiation and disturb the intricate balance between proliferation and differentiation state of keratinocytes in the skin. To understand the effect of TRPV3 mutation, transcriptome of 293T cell lines transfected with mutant TRPV3 were profiled in time-course manner (16, 24 and 40hr).
2013-12-24 | E-GEOD-53614 | biostudies-arrayexpress
Project description:The goal of our study was to determine the effect of overexpressing TRPV3 in the lung epithelial cell line BEAS-2Bs. BEAS-2B cells, were transfected with hTRPV3 in pcDNA3.1V5/His and stable overexperssion was achieved using antibiotic selection (G418). Comparisons were between treatments in wild-type cells vs those overexperssing TRPV3.
2018-04-26 | GSE109598 | GEO
Project description:Background: Anti-type 2 cytokine therapies represent promising interventions for chronic itch; however, their precise mechanisms in restoring nerve architecture and mitigating inflammation and pruritus remain incompletely understood. This study aimed to elucidate the mechanistic roles of IL-4, IL-13, and IL-31 in the pathophysiology of itch associated with type 2 inflammatory skin diseases. Methods: The effect of IL-4, IL-13, and/or IL-31 on neurite outgrowth and/or transcriptomic changes were analyzed in human and mouse dorsal root ganglion (DRG) neuronal cultures. Mouse ear pinnae were processed for histologic, transcriptomic, and proteomic analyses 4 days after intradermal injection of IL-4, IL-13, and/or IL-31. To evaluate functional correlations with neuronal responses, mice were subcutaneously challenged with IL-4, IL-13, and/or IL-31, and scratching behavior was monitored. Association between IL-4/IL-13–IL-4Rα axis and severity of atopic dermatitis (AD) was evaluated through correlative analyses of human DRG transcriptomic changes and AD transcriptomic datasets (GSE130588 and BioMap consortium). Results: IL-4 and IL-13 promote mouse and human DRG sensory neuron growth, with effects similar to or greater than IL-31. In mice, intradermal IL-4, IL-13, and IL-31 increased epidermal nerve growth; however, only IL-4 and IL-13 induced hyperplasia and immune cell recruitment. Multi-omic analyses revealed that IL-4 and IL-13 have a broader impact on neuroimmune interactions than IL-31. In a murine DRG neuron-eosinophil co-culture, IL-4Rα blockade reduced neurite growth. IL-13 and IL-31 elicited acute scratching, demonstrating their roles as direct pruritogens; IL-4 synergistically enhanced IL-13-induced itch, resulting in greater pruritic responses than IL-31. Additionally, a set of itch-associated genes upregulated by IL-4 and IL-13 and downregulated by dupilumab-mediated IL-4Rα blockade in human DRG neuronal cultures showed positive correlation with AD severity. Conclusions: These findings establish the IL-4/IL-13–IL-4Rα axis as a key regulator of inflammatory skin nerve innervation, neuroimmune interactions, barrier integrity, and itch response, highlighting its mechanistic role in modulating sensory neuronal function and shaping the inflammatory microenvironment that drives itch pathophysiology.
2025-05-15 | GSE296776 | GEO
Project description:Background: Anti-type 2 cytokine therapies represent promising interventions for chronic itch; however, their precise mechanisms in restoring nerve architecture and mitigating inflammation and pruritus remain incompletely understood. This study aimed to elucidate the mechanistic roles of IL-4, IL-13, and IL-31 in the pathophysiology of itch associated with type 2 inflammatory skin diseases. Methods: The effect of IL-4, IL-13, and/or IL-31 on neurite outgrowth and/or transcriptomic changes were analyzed in human and mouse dorsal root ganglion (DRG) neuronal cultures. Mouse ear pinnae were processed for histologic, transcriptomic, and proteomic analyses 4 days after intradermal injection of IL-4, IL-13, and/or IL-31. To evaluate functional correlations with neuronal responses, mice were subcutaneously challenged with IL-4, IL-13, and/or IL-31, and scratching behavior was monitored. Association between IL-4/IL-13–IL-4Rα axis and severity of atopic dermatitis (AD) was evaluated through correlative analyses of human DRG transcriptomic changes and AD transcriptomic datasets (GSE130588 and BioMap consortium). Results: IL-4 and IL-13 promote mouse and human DRG sensory neuron growth, with effects similar to or greater than IL-31. In mice, intradermal IL-4, IL-13, and IL-31 increased epidermal nerve growth; however, only IL-4 and IL-13 induced hyperplasia and immune cell recruitment. Multi-omic analyses revealed that IL-4 and IL-13 have a broader impact on neuroimmune interactions than IL-31. In a murine DRG neuron-eosinophil co-culture, IL-4Rα blockade reduced neurite growth. IL-13 and IL-31 elicited acute scratching, demonstrating their roles as direct pruritogens; IL-4 synergistically enhanced IL-13-induced itch, resulting in greater pruritic responses than IL-31. Additionally, a set of itch-associated genes upregulated by IL-4 and IL-13 and downregulated by dupilumab-mediated IL-4Rα blockade in human DRG neuronal cultures showed positive correlation with AD severity. Conclusions: These findings establish the IL-4/IL-13–IL-4Rα axis as a key regulator of inflammatory skin nerve innervation, neuroimmune interactions, barrier integrity, and itch response, highlighting its mechanistic role in modulating sensory neuronal function and shaping the inflammatory microenvironment that drives itch pathophysiology.
2025-05-15 | GSE296778 | GEO