Cell Activation Research Articles (Page 1)

Triple-TLR agonists' adjuvanted inactivated Newcastle disease virus vaccine promotes effective Th1/Th2 immune responses and affords protective efficacy in chickens.

Helixor A enhances natural killer cell activity by induction of PAI-1 expression through the p38/MAPK signaling pathway.

Abstract Androgenic alopecia (AGA), the most common form of progressive hair loss in both males and females, significantly impacts patients’ quality of life and confidence. Current therapies, such as minoxidil, are limited by poor patient compliance and low transdermal bioavailability, highlighting the need for more effective treatments. In this study, we identified collagen XVII (COL17) as a key player in AGA-like model pathogenesis, observing its significant downregulation in a testosterone-induced AGA-like mouse model. This reduction was accompanied by abnormal hair follicle morphology, decreased proliferation, and impaired angiogenesis. To address this, we developed recombinant human COL17 fragment (800–1300 aa) (rhCOL17p) expressed and purified from E. coli, which demonstrated dose-dependent enhancement of dermal papilla cell adhesion, migration, and proliferation in vitro. To overcome transdermal delivery challenges, we designed a dissolving microneedle (MN) patch using hyaluronic acid as a matrix. The rhCOL17p-MN achieved 96% skin penetration and sustained release of 96% within 28 h in vitro, with residual fluorescence detectable in mouse skin for up to 6 days. In vivo, the 4 mg/mL rhCOL17p-MN achieved a mean hair coverage of approximately 97% by day 14, which was statistically equivalent to the efficacy of 5% minoxidil, with increased follicle density, anagen-phase transition, and CD31+ vascularization. Histological analysis revealed restored follicle structure and upregulated β-catenin+ and SRY-box gene 9 (SOX9+), indicating activation of stem cell and proliferative signaling pathways. The rhCOL17p-MN also demonstrated low hemolysis (< 0.5%) and robust mechanical stability (≥ 0.2 N/needle), confirming its safety and feasibility. These findings establish COL17 downregulation as a critical mechanism in AGA and demonstrate that MN-delivered rhCOL17p promotes hair regeneration through multi-pathway regulation, offers preclinical evidence supporting its potential as a candidate strategy for further investigation in AGA-related research.

Liver cirrhosis is a progressive chronic disease with high morbidity and mortality, thereby posing a major challenge to global health. Evidence suggests that thyroid dysfunction, particularly hypothyroidism, is linked to liver diseases. Hypothyroidism disrupts metabolism, immune homeostasis, and inflammatory pathways, processes central to cirrhosis pathophysiology. However, its causal role and molecular mechanisms remain unclear. The study initiated by analyzing the association between thyroid dysfunction and cirrhosis through retrospective analysis of longitudinal data obtained from the Medical Information Mart for Intensive Care clinical database. To assess genetic correlation, we applied linkage disequilibrium score regression, followed by bidirectional Mendelian randomization to explore potential causal relationships. Through transcriptome-wide association studies, we identified candidate genes, which were then prioritized using a combination of weighted gene co-expression network analysis and differential gene expression data integration. To interpret the biological relevance of these genes, we conducted functional enrichment analyses. We further explored gene function at the cellular level by leveraging single-cell RNA sequencing (scRNA) to map cell-specific expression patterns, analyze intercellular communication, and simulate gene knockouts. Finally, we performed molecular docking and phenome-wide Mendelian randomization to identify potential therapeutic compounds targeting the prioritized genes. Through a combination of observational and genetic insights, we established a causal relationship between hypothyroidism and cirrhosis, identifying hypothyroidism as a risk factor for cirrhosis. Subsequent multi-omics analyses highlighted HLA-DQA1 and CD27 as potential therapeutic targets. ScRNA revealed key roles of these molecules in macrophages and CD8 ⁺ T cells, and simulated knockouts confirmed their importance in T cell activation and lymphocyte proliferation. Finally, molecular docking analysis identified glycyrrhizic acid and levothyroxine sodium as candidate drugs targeting HLA-DQA1 and CD27, while phenome-wide Mendelian randomization analysis revealed potential adverse effects associated with these targets. This study is the first to reveal a causal relationship between hypothyroidism and cirrhosis, potentially driven by immune dysregulation mediated by HLA-DQA1 and CD27. These findings offer novel insights into disease progression and identify HLA-DQA1 and CD27 as potential therapeutic targets, with glycyrrhizic acid and levothyroxine sodium as promising candidate drugs.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune exocrinopathy affecting salivary and lacrimal glands. This study presents an exploratory single-cell transcriptomic analysis of labial salivary glands to generate hypotheses about B-cell-associated gene modules in pSS, and to uncover novel therapeutic targets for B cell modulation in pSS. The high-dimensional weighted gene co-expression network analysis (hdWGCNA) was performed on gene expression data obtained from single-cell RNA sequencing (scRNA-seq) of 32,337 cells from labial glands of three pSS patients and three healthy controls. Gene Ontology (GO) enrichment analysis was subsequently conducted to investigate the functional roles of the identified gene modules. Additionally, the scRank method was applied to evaluate the responsiveness of key B cell-related targets across different cell types, providing new insights into the role of B cells in the pathogenesis of pSS. Through hdWGCNA analysis, we resolved seven co-expression modules in pSS. Module 5, restricted to plasma cells, contains POU2AF1, SLAMF7, SPCS2, CD79A and PDIA6 and is highly enriched for COPI/II-mediated vesicle trafficking and B-cell-receptor signaling, thereby driving autoantibody production and chronic inflammation. Modules 1, 2, 4, 6 and 7 align with extracellular-matrix remodeling, epithelial stress and metabolic reprogramming, underscoring the disease's multifactorial pathobiology. scRank ranked Module 5 as the most drug-responsive cluster and highlighted POU2AF1, SLAMF7 and CD79A as tractable B-cell targets for restoring immune homeostasis in pSS. Our study identified distinct gene modules associated with pSS, with a particular emphasis on B cells, unveiling novel potential therapeutic targets. The activation of B cells, coupled with immune dysregulation and epithelial dysfunction, appears to play a critical role in pSS pathogenesis, offering valuable insights for developing targeted therapeutic strategies that address both immune activation and tissue repair. These findings nominate B-cell-associated modules-including a plasma cell-enriched module featuring POU2AF1, SLAMF7, and CD79A-as hypotheses for future functional validation.

Ammonia-induced T lymphocyte death (AITD) offers a new perspective on immune regulation after the activation of CD8+ T cells. However, the use of a single AITD inhibitor is constrained by multiple factors in the immunosuppressive tumor microenvironment and requires combination strategies to achieve breakthroughs. Herein, a rationally designed organic nanozyme (IR-IHpd) is presented, integrating anthocyanin-based near-infrared photodynamic therapy (NIR-PDT) and Hemin-derived peroxidase (POD)-like catalytic activity. Under 780nm laser irradiation, it generates ROS through Type I/II photodynamic mechanisms while catalyzing H2O2 into cytotoxic ·OH, establishing an uninterrupted ROS generation. Co-encapsulated with CB-839 in DSPE-Hyd-PEG and coated with dendritic cell (DC) membranes to form a biomimetic system (DMIC), this system targets both tumors and T cells. After intravenous administration, the DMIC nanozyme system efficiently accumulates in tumor tissues, tumor-draining lymph nodes, and spleens, where NIR irradiation induces tumor immunogenic cell death while promoting DCs maturation and T cell activation. The DMIC also functions as a tumor vaccine, capable of directly activating T cells and preventing tumor occurrence. Furthermore, the released CB-839 reduces intracellular ammonia levels in T cells, thereby enhancing anti-tumor immunity. This pioneering work achieves targeted AITD inhibition for the first time, integrating NIR-PDT, metabolic modulation, and immune activation to advance nanozyme-based immunotherapy.

Alternate splicing converts human CD137 from costimulatory to immunosuppressive function.

Insulin-producing β cell replacement therapies show promise for treating type 1 diabetes (T1D), but challenges such as donor shortages and immune rejection persist. Stem cell-derived β cells (sBC) provide a renewable source but remain susceptible to immune attack. We engineered human pluripotent stem cells to express either the wild type (WT) or a high-affinity mutant (Mut) variant (rs1058402, G>A; Ala67Thr) of the natural killer (NK) and T cell checkpoint inhibitor CD155 before differentiation into sBC. Modified sBC maintained up-regulated CD155 expression and showed enhanced binding to co-receptor ligands. Co-culture studies revealed CD155-expressing sBC suppressed autoreactive CD8+ T cell and NK cell activation, reducing immune cell-mediated sBC destruction and cytotoxic molecule secretion by preferentially engaging the coinhibitory receptor TIGIT. This protection was lost with TIGIT blockade, affirming the role of CD155-TIGIT signaling in antagonizing immune cell cytotoxicity. Our findings suggest that high-affinity CD155 expression enhances immune evasion of sBC, improving their potential as a therapy for T1D.

Developing a therapeutic elastase that stimulates anti-tumor immunity by selectively killing cancer cells.

Alzheimer's disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-βeta (Aβ) peptides and hyperphosphorylated tau protein. Altered sphingosine 1-phosphate(S1P) metabolism is associated with abnormal Aβ peptide accumulation in the brain. S1P receptorsare increasingly being targeted for modulating the neuroinflammatory process in AD. Wild-type male C57BL/6J mice were administered Aβ to induce the pathological state. The study included four experimental groups: (1) Control group (saline-treated), (2) Aβ group (Aβ + saline-treated), (3) Aβ + cP1P group (Aβ + cP1P at doses of 0.1 mg/kg and 1 mg/kg), and (4) Aβ+ P1P group (Aβ + P1P at doses of 0.1 mg/kg and 1 mg/kg). Behavioral experiments were conducted to assess cognitive and memory functions. Additionally, western blotting and confocal microscopy were performed to investigate molecular and cellular changes. The findings demonstrate that administration of S1P analogs cP1P and P1P at 0.1 mg/kg and 1 mg/kg significantly reduced Aβ burden by inhibiting the amyloidogenic pathway and decreasing hyperphosphorylated tau protein levels in the mouse brain. Additionally, cP1P and P1P inhibited glial cell activation, as indicated by reduced GFAP and Iba-1 expression, and modulated neuroinflammatory markers, including p-NF-κB, TNF-α, and IL-1β. Furthermore, they regulated S1PR1-mediated Akt/mTOR signaling while preserving mitochondrial function by decreasing the expression levels of p-JNK, Caspase-3, and PARP-1. Moreover, the cP1P and P1P effectively restored synaptic markers such as PSD-95, SNAP-25, and Syntaxin, and significantly improved behavioral outcomes in the Aβ-treated mice. In vitro, results also demonstrated that the novel cP1P and P1P enhanced cell viability against Aβ toxicity.

Chronic glomerulonephritis is a prevalent renal disorder in clinical practice. A metabolic imbalance in copper, a vital trace element in the human body, is potentially linked to a myriad of diseases. Consequently, this study aimed to elucidate the role of copper metabolism in the onset and progression of chronic glomerulonephritis. Public microarray datasets gene expression omnibus series(GSE) 66494, GSE32591, and GSE116626 were procured from the gene expression omnibus database, encompassing clinical information on chronic glomerulonephritis and normal kidney tissues. Differential gene expression analysis was conducted, followed by the intersection of the differentially expressed genes from the 3 datasets with those related to copper metabolism. Furthermore, STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network; PPI hub genes were identified via the cytoHubba plugin, and gene set enrichment analysis was performed. Tissues were subsequently collected from chronic glomerulonephritis patients at our hospital; hematoxylin and eosin, periodic acid-silver methenamine, and Masson staining were conducted; and transmission electron microscopy was performed. Pivotal genes were selected for real time quantitative polymerase chain reaction (PCR) (RT-qPCR) validation, and serum copper ion levels were measured. Additionally, CIBERSORT analysis was employed to assess immune cell infiltration and its correlation with pivotal genes. Differential gene expression analysis revealed 25 differentially expressed copper metabolism-related genes (CMRGs), comprising 11 upregulated genes and 14 downregulated genes. PPI network construction and gene correlation analysis ultimately identified aconitase (ACO1) and superoxide dismutase (SOD2) as pivotal genes for RT-qPCR validation. The results demonstrated that ACO1 was expressed at low levels in lupus nephritis tissues, whereas SOD2 was highly expressed in immunoglobulin A nephropathy and diabetic nephropathy tissues. Moreover, immune infiltration analysis revealed that diverse immune cell types, including T cells, B cells, and macrophages, are intricately associated with the onset and progression of chronic glomerulonephritis in patient tissues. Differential and correlation analyses of CMRGs revealed that T cells, plasma cells, and monocyte-macrophages are involved in the biological processes of copper metabolism. This study suggests that the CMRGs ACO1 and SOD2 may modulate the inflammatory response and immune microenvironment in chronic glomerulonephritis by regulating immune cell activation and function, thereby facilitating disease progression.

Metastatic progression is a major cause of radiotherapy (RT) failure, yet the mechanisms linking RT to immune suppression and metastasis remain unclear. Here, we identify YTHDF2 as a radiation-induced immune checkpoint in dendritic cells (DCs). By analyzing patient biopsies from a clinical trial (NCT03223155), we discover that increased YTHDF2 expression in DCs after RT correlates with treatment failure after RT. Mechanistically, ionizing radiation induces SPI1, which drives transcription of Ythdf2 in DCs. Upregulated YTHDF2 promotes m6A-mediated degradation of Notch pathway regulators (Mfng, Aph1b, Aph1c), impairing MHC-I cross-presentation and CD8+ T cell activation, thereby facilitating tumor immune evasion and metastatic spread. Crucially, targeting YTHDF2 restores DC immunogenicity, enhances RT-induced tumor control, and improves DC-based cancer vaccines when combined with RT, providing a clinically actionable strategy to overcome RT resistance and metastasis.

To address suboptimal antibody induction by commercial PEDV vaccines, we constructed a recombinant adeno-associated virus (rAAV-CMV-PEDV S1) expressing regions of the PEDV S1 subunit based on Adeno-associated virus serotype 2 (AAV-2) vector. In mice, rAAV-CMV-PEDV S1 induced significantly more remarkable and persistent serum-specific IgG compared with the inactivated vaccine and accompanied by robust CD3+CD8+ T cells activation within 4 weeks post-immunization. In pregnant sows, compared with commercially available inactivated and attenuated vaccines, the rAAV-CMV-PEDV S1 induced significantly higher serum and colostral IgG as well as neutralizing antibody titers, which provided piglets with abundant maternal antibodies. Crucially, challenge experiments demonstrated that rAAV-CMV-PEDV S1 conferred 80% clinical protective efficacy for piglets, accompanied by significantly reduced viral shedding loads, surpassing other vaccine groups. These findings suggest that rAAV-CMV-PEDV S1 candidate could be a promising PEDV vaccine for enhancing antibody levels and could strengthen the protection of piglets against PEDV infection.

Background: We recently generated T cell receptor (TCR) transgenic (Tg) mice specific to cardiac myosin heavy chain-α (Myhc-α 334–352) on both myocarditis-resistant (C57BL/6) and susceptible (A/J) genetic backgrounds. We noted that the antigen-specific TCRs were expressed in CD4+ and CD8+ T cells in both strains, but their responses differed. While the T cells from naïve Tg C57BL/6 mice do not respond to Myhc-α 334–352, whereas those from A/J mice spontaneously respond to the antigen, suggesting their underlying molecular mechanisms might differ. Methods: To investigate the mechanisms of differences in the antigen-responsiveness between the Tg C57BL/6 and A/J mice, we performed bulk RNA sequencing on CD4⁺ and CD8⁺ T cells sorted by flow cytometry. Differentially expressed genes, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, gene set enrichment analysis (GSEA) of GO and KEGG, and transcription factor (TF) network analyses were performed to identify pathways and regulators of immune responses. Results: First, the principal component analysis of the transcriptomic profiles distinguished CD4+ from CD8+ T cells, which also differed between the two strains. Second, the differentially expressed cytokine and cytotoxicity genes revealed similar patterns between CD4+ and CD8+ T cells. Importantly, KEGG enrichment analysis revealed downregulated pathways in both CD4+ and CD8+ T cells that are associated with viral myocarditis, and various autoimmune conditions in C57BL/6 as compared to A/J mice. Similarly, the GSEA of GO revealed negative regulation of heart contraction and positive regulation of cardiac muscle hypertrophy processes were negatively enriched in CD4+ T cells of C57BL/6 mice. Finally, by generating the transcription factor (TF) networks, 22 TFs were found common to both CD4+ and CD8+ T cells, whereas eight TFs were unique to CD4+ or CD8+ T cells that have a role in T cell activation, tolerance, and T regulatory cells. Conclusions: Our data provide new insights into the transcriptomic profiles that may contribute to the genetic resistance mechanisms for developing cardiac autoimmunity.

Background Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TILs) is a personalized immunotherapy that has shown promising clinical results in various tumor types. Although TILs are associated with improved survival in patients with ovarian cancer (OC), their therapeutic efficacy remains limited. Therefore, novel strategies to enhance the anti-tumor activity of TILs are needed to improve outcomes in OC treatment. Methods Single cells were isolated from tumor tissues of patients with high-grade serous carcinoma (HGSC) and expanded for 14 days in the presence of IL-2 under four different conditions: (1) control (W), (2) PD-1 antagonist (WI), (3) PD-1 antagonist + IL-15 + IL-21 (WIO), and (4) PD-1 antagonist + IL-15 + IL-21 + GITR-agonist (WIOG). Following validation of TIL purity and activation phenotypes by flow cytometry, RNA sequencing was performed to elucidate the underlying mechanisms. In vitro efficacy was assessed using a 7-AAD/Far-Red cytotoxicity assay against autologous tumor cells, and in vivo efficacy was evaluated in NSG mice bearing subcutaneous patient-derived tumor cell xenografts (PDCX). Results On day 14, the WIOG group showed a 1.3-fold increase in expansion compared to the control group, along with a high CD8 + /Treg ratio (454.6). Furthermore, both CD8 + and CD4 + T cells in the WIOG group exhibited elevated Granzyme B expression. RNA sequencing identified 279 upregulated genes associated with T cell activation ( CSF2, TNFRSF4 ), cytotoxicity ( IFNG, GZMB ), and anti-apoptosis ( BMF, BCL2L1 ). Compared to the controls, the WIOG group demonstrated a 1.9-fold increase in cytolytic activity in vitro and a 56% reduction in tumor growth in the patient-derived tumor cell xenograft (PDCX) model. Conclusions Taken together, we demonstrated that the addition of an agonistic GITR antibody during the early phase of TIL culture increased the CD8 + T cell to Treg cell ratio and enhanced anti-tumor T cell immunity. Enhancing TILs with a GITR agonist may be beneficial for improving the clinical outcomes of TIL-based ACT in OC.

Cannabis cigarette smoking disrupts mice multi-organ bioactive lipid metabolism and inflammation-resolution signaling in an obesogenic setting.

Sepsis-induced endothelial dysfunction, marked by degradation of the endothelial glycocalyx and activation of endothelial cells, plays a pivotal role in the progression to organ failure and mortality. Biomarkers reflecting glycocalyx damage have demonstrated prognostic potential; however, their associations with clinical outcomes remain variable. We systematically evaluated the prognostic utility of glycocalyx-associated biomarkers (syndecan-1, heparan sulfate, hyaluronate) and the endothelial activation marker endocan in sepsis with respect to mortality, organ dysfunction, and inter-study heterogeneity. We included 23 studies through May 2025 encompassing 4529 patients with sepsis. Two independent reviewers extracted data using standardized protocols, including biomarker concentrations and clinical outcomes such as mortality, multiple organ dysfunction syndrome, and respiratory failure. Risk of bias was assessed using the NOS, with 75% of studies rated as low risk. Elevated syndecan-1 was significantly associated with increased mortality (nine studies, n = 2167; OR 2.04, 95% CI, 1.66-2.51; p < 0.05; I² = 84%). Similarly, elevated endocan predicted mortality with a stronger effect size (six studies, n = 435; OR 5.06, 95% CI, 2.52-10.18; p < 0.05) and low heterogeneity. In contrast, syndecan-1 levels were not significantly associated with multiple organ dysfunction syndrome (OR 2.35, 95% CI, 0.93-5.94; I² = 94%) or respiratory failure (OR 1.05, 95% CI, 0.27-4.02; I² = 91%). The majority of studies were ICU-based (78.3%), primarily adult cohorts (91.3%), with syndecan-1 the most commonly assessed biomarker (65.2%). Syndecan-1 and endocan serve as prognostic biomarkers for mortality in sepsis, with endocan demonstrating greater inter-study consistency.

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.

Minocycline, a semisynthetic tetracycline, is widely used to treat inflammatory skin diseases such as acne and rosacea. Despite its favorable safety profile, it may cause various adverse effects, including hypersensitivity reactions. We describe the case of a 20-year-old male who developed delayed-onset symptomatic dermographism following oral minocycline treatment (100 mg/day) for acne. One week after starting treatment, the patient developed pruritic, evanescent, linear wheal-like lesions at multiple sites, without angioedema or systemic symptoms. Lesions resolved spontaneously within two weeks of drug withdrawal. An oral challenge test with escalating doses of minocycline, up to a cumulative total of 100 mg initially, showed tolerance; however, symptoms recurred after nine consecutive days at the therapeutic dose, confirming causality. Symptoms resolved following drug discontinuation and a 2-day course of oral cetirizine. To evaluate cross-reactivity, prick and intradermal tests with doxycycline were negative, and a 10-day oral doxycycline challenge was uneventful, indicating no cross-reactivity. Symptomatic dermographism is the most common form of chronic inducible urticaria, but its association with minocycline is rare. The underlying immunopathogenesis remains unclear, potentially involving mast cell activation or superantigen-like effects. This case underscores the importance of prolonged drug rechallenge in identifying rare delayed adverse reactions such as minocycline-induced late-onset symptomatic dermographism and supports the safe use of doxycycline as an alternative.

The current treatment of provoked vestibulodynia involving neuroproliferation is often complete vestibulectomy; however, less invasive treatments are biologically plausible, yet lack study. The International Society for the Study of Women's Sexual Health, the National Vulvodynia Association, the Gynecologic Cancers Research Foundation, and Tight Lipped, a grassroots nonprofit organization that supports people with chronic vulvovaginal and pelvic pain, collectively sponsored a conference, the Vulvodynia Therapeutic Research Summit, held in April 2024. The primary objective of the Vulvodynia Therapeutic Research Summit was to identify options for further research of the treatment of provoked vestibulodynia through expert consensus. After the conference, attendees scored the presented therapeutics in rank order, leading to a hierarchy of merit. Fifteen therapeutic options were presented and ranked in order of most promising to least promising for further study on treating the neuroinflammation of provoked vestibulodynia. The top identified therapeutics for further research were: 1) ketotifen fumarate (mast cell stabilizer with potential to prevent mast cell activation), 2) resiniferatoxin (transient receptor vanilloid 1 agonist causing chemo-inactivation of nerve terminals), 3) specialized pro-resolving mediators or strategies to boost their levels (eg, maresin 1 and 1-trifluoromethoxy-phenyl-3-(1-propionylpiperidin-4-yl) urea), 4) luteolin (flavonoid with potent anti-inflammatory, antioxidant, and neuroprotective properties), 5) alpha-lipoic acid (antioxidant with nerve-specific anti-inflammatory and mast cell stabilizing qualities), and 6) NGFR121W-SNAP IR700 trimer exposed to near-infared light (photoablation targeting nociceptors and sparing surrounding tissue). This executive summary describes the rationale for identifying specific pharmacologic agents and medical devices as targets for research directed toward treatment of the neuroinflammatory process found in the vestibular mucosa of provoked vestibulodynia.