Cutaneous Responses Research Articles

Nuclear versus cytoplasmic IKKα signaling in keratinocytes leads to opposite skin phenotypes and inflammatory responses, and a different predisposition to cancer.

IKKα is known as an essential protein for skin homeostasis. However, the lack of suitable models to investigate its functions in the skin has led to IKKα being mistakenly considered as a suppressor of non-melanoma skin cancer (NMSC) development. In this study, using our previously generated transgenic mouse models expressing exogenous IKKα in the cytoplasm (C-IKKα mice) or in the nucleus (N-IKKα mice) of basal keratinocytes, we demonstrate that at each subcellular localization, IKKα differently regulates signaling pathways important for maintaining the balance between keratinocyte proliferation and differentiation, and for the cutaneous inflammatory response. In addition, each type of IKKα-transgenic mice shows different predisposition to the development of spontaneous NMSC. Specifically, N-IKKα mice display an atrophic epidermis with exacerbated terminal differentiation, signs of premature skin aging, premalignant lesions, and develop squamous cell carcinomas (SCCs). Conversely, C-IKKα mice, whose keratinocytes are nearly devoid of endogenous nuclear IKKα, do not develop skin SCCs, although they exhibit hyperplastic skin with deficiencies in terminal epidermal differentiation, chronic cutaneous inflammation, and constitutive activation of STAT-3 and NF-κB signaling pathways. Altogether, our data demonstrate that alterations in the localization of IKKα in the nucleus or cytoplasm of keratinocytes cause opposite skin changes and differentially predispose to the growth of skin SCCs.

Reverse-engineered models reveal differential membrane properties of autonomic and cutaneous unmyelinated fibers.

Unmyelinated C-fibers constitute the vast majority of axons in peripheral nerves and play key roles in homeostasis and signaling pain. However, little is known about their ion channel expression, which controls their firing properties. Also, because of their small diameters (~ 1 μm), it has not been possible to characterize their membrane properties using voltage clamp. We developed a novel library of isoform-specific ion channel models to serve as the basis functions of our C-fiber models. We then developed a particle swarm optimization (PSO) framework that used the isoform-specific ion channel models to reverse engineer C-fiber membrane properties from measured autonomic and cutaneous C-fiber conduction responses. Our C-fiber models reproduced experimental conduction velocity, chronaxie, action potential duration, intracellular threshold, and paired pulse recovery cycle. The models also matched experimental activity-dependent slowing, a property not included in model optimization. We found that simple conduction responses, characterizing the action potential, were controlled by similar membrane properties in both the autonomic and cutaneous C-fiber models, but complicated conduction response, characterizing the afterpotenials, were controlled by differential membrane properties. The unmyelinated C-fiber models constitute important tools to study autonomic signaling, assess the mechanisms of pain, and design bioelectronic devices. Additionally, the novel reverse engineering approach can be applied to generate models of other neurons where voltage clamp data are not available.

Pilonidal granuloma formation after an incision and drainage procedure is associated with retained hair within the sinus – A case series

Introduction and importancePilonidal disease may present with a draining secondary sinus or granuloma, but the development of these findings is not well-characterized. Case presentationTwo adolescent males presented with pilonidal disease. The first patient had a gluteal cleft abscess, and an incision and drainage procedure was performed. Although the abscess resolved, the incision site formed a granuloma with intermittent draining wound with granulation tissue. He underwent a pit-picking procedure along with excision of the granuloma. A large amount of hair was also removed from within the pilonidal sinus. The second patient underwent an incision and drainage procedure to treat the pilonidal abscess. The incision site evolved into a granuloma with recurring drainage. A pit-picking procedure was performed, and the granuloma was excised. During the excision, a moderate amount of hair was evacuated from the pilonidal sinus. Clinical discussionMany pilonidal patients present with a granuloma or secondary sinus at the gluteal cleft, but there has been no documentation of the natural history of this development. The role of hair is central to pilonidal disease pathophysiology and is a known factor in foreign body granuloma formation – a cutaneous inflammatory response to endogenous or exogenous material in the dermis that is not broken down readily by macrophages. ConclusionEven though the pilonidal abscess was drained with an incision, a granuloma was able to form with recurrent drainage when hair was retained within the pilonidal sinus.

Impaired microvascular insulin-dependent dilation in women with a history of gestational diabetes.

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10-10-10-1 M) and insulin (10-8-10-4 M) in control sites and sites treated with 15 mM l-NAME [NG-nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine (P = 0.006) and insulin (P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC (P = 0.009) but had no effect in GDM (P = 0.306). Ascorbate treatment increased acetylcholine (P < 0.001)- and insulin (P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC (P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance.NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Critical role of keratinocytes in cutaneous immune responses

Keratinocytes play an integral role in the human epidermis, serving as a barrier between the internal and external environment. They are immune-competent cells involved in both innate and adaptive cutaneous immune responses, crucial for maintaining skin integrity. Keratinocytes are essential for epidermal repair, facilitating proliferation and re-epithelialization following injury. They secrete pro-inflammatory markers such as cytokines and chemokines, which promote the recruitment of inflammatory cells like polymorphs and macrophages to the site of skin injury. The immune response mediated by keratinocytes involves signaling molecules like tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6. Langerhans cells respond to factors secreted by keratinocytes, migrating towards draining lymph nodes to activate T cells and initiate an adaptive immune response. Additionally, keratinocytes express Toll-like receptors (TLRs), enabling them to detect molecular patterns of pathogens. Recent studies have focused on understanding these interactions of keratinocytes to develop therapeutic strategies for managing various skin diseases. Genetic defects in keratinocytes underlie conditions like psoriasis. We also discuss the role of keratinocytes and the effect of neuro-endocrinal signaling and interventions, associated corticosteroidogenic pathways, and response to UV radiations to maintain a state of homeostasis. This article underlines and improves our understanding of the immune function of keratinocytes, which is crucial for developing more effective therapies against skin diseases.

Drug-Induced Sweet’s Syndrome by Xcopri

Background: Sweet's syndrome (SS) is a relatively rare, self-limiting dermatological condition predominantly affecting women aged 30-50. It is characterized by the sudden onset of erythematous plaques, nodules, or papules on the skin and is often accompanied by fever, leukocytosis, and systemic symptoms. While most SS cases are idiopathic, approximately 5% are drug-induced. Case: This case report describes a 34-year-old female with a medical history significant for epilepsy who presented with diffuse erythematous papules on the bilateral upper extremities. The onset of these symptoms coincided with the initiation of Xcopri (cenobamate tablets) in her medication regimen. Conclusion: To our knowledge, this report highlights the first case of Xcopri-induced SS. We interpret this patient's presentation as a cutaneous response secondary to an adverse drug reaction and aim to emphasize the importance of obtaining a thorough medication history at each clinical consultation.

Exploring the Effects of an Alfalfa Leaf-Derived Adsorbent on Microbial Community, Ileal Morphology, Barrier Function, and Immunity in Turkey Poults during Chronic Aflatoxin B1 Exposure.

This article follows-up on our recently published work, which evaluated the impact of the addition of an alfalfa leaf-derived adsorbent in the aflatoxin B1 (AFB1)-contaminated diet in regard to the production parameters, blood cell count, serum biochemistry, liver enzymes, and liver histology of turkey poults. This paper presents complementary results on microbial community, ileal morphology, barrier function, and immunity. For this purpose, 350 1-day-old female turkey poults were randomly distributed into five groups: (1) Control, AFB1-free diet; (2) AF, AFB1-contaminated diet at 250 ng/g; (3) alfalfa, AFB1-free diet + 0.5% (w/w) adsorbent; (4) alfalfa + AF, AFB1-contaminated diet at 250 ng/g + 0.5% (w/w) adsorbent; and (5) YCW + AF, AFB1-contaminated diet at 250 ng/g + 0.5% (w/w) commercial yeast cell wall-based adsorbent (reference group). In general, in the AF group, the growth of opportunistic pathogens was promoted, which lead to gut dysbacteriosis, mainly influenced by Streptococcus lutetiensis. Conversely, a significant increase in beneficial bacteria (Faecalibacterium and Coprococcus catus) was promoted by the addition of the plant-based adsorbent. Moreover, the AF group had the lowest villus height and a compromised barrier function, as evidenced by a significant (p < 0.05) increase in fluorescein isothiocyanate dextran (FITC-d), but these negative effects were almost reversed by the addition of the alfalfa adsorbent. Furthermore, the AF + YCW and alfalfa + AF groups exhibited a significant increase in the cutaneous basophil hypersensitivity response compared to the rest of the experimental groups. Taken together, these results pointed out that the alfalfa counteracts the adverse effects of AFB1 in poults, facilitating the colonization of beneficial bacteria and improving the barrier function of the turkey poults.

Effect of benralizumab on inflammation in skin after intradermal allergen challenge in patients with moderate-to-severe atopic dermatitis

BackgroundAtopic dermatitis is a skin barrier dysfunction characterized by tissue eosinophilia. Objective: In patients with atopic dermatitis (AD) we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. Methods20 patients with moderate to severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses q4wk 30 mg subcutaneous benralizumab (n=9) to placebo (n=11). Allergen and saline control intradermal challenges were conducted before and after treatment with skin biopsies collected 24 hours after challenge. Early (ECR) and late cutaneous responses (LAR) were measured by skin wheal size. Eosinophils and IL-5Rα -bearing cells including eosinophil progenitor cells (EoP), basophils and mast cells were measured in papillary dermis by immunofluorescence microscopy, and EoP, hemopoietic progenitor cells (HPC) and ILC2 were measured in blood by flow cytometry. Outcomes were compared between placebo and benralizumab treatment groups using Mann-Whitney U-test. ResultsBenralizumab reduced eosinophils in blood (p<0.0001), and allergen challenged skin as measured by H&E and EG2 (p<0.05). Benralizumab lowered levels of EoP, mast cells and basophil numbers in skin, as well as EoP, HPC and ILC2s in blood (all p<0.05). There was a trend for improvement in the ECR response (p=0.095), but no effect on the LCR. ConclusionIn patients with moderate to severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5Rα expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5Rα positive cells did not modulate the size of the allergen-induced skin wheal. (ClincialTrials.gov number, NCT03563066).

Postbiotic lactobacilli induce cutaneous antimicrobial response and restore the barrier to inhibit the intracellular invasion of Staphylococcus aureus invitro and exvivo.

Intracellular pathogens including Staphylococcus aureus contribute to the non-healing phenotype of chronic wounds. Lactobacilli, well known as beneficial bacteria, are also reported to modulate the immune system, yet their role in cutaneous immunity remains largely unknown. We explored the therapeutic potential of bacteria-free postbiotics, bioactive lysates of lactobacilli, to reduce intracellular S. aureus colonization and promote healing. Fourteen postbiotics derived from various lactobacilli species were screened, and Latilactobacillus curvatus BGMK2-41 was selected for further analysis based on the most efficient ability to reduce intracellular infection by S. aureus diabetic foot ulcer clinical isolate and S. aureus USA300. Treatment of both infected keratinocytes invitro and infected human skin exvivo with BGMK2-41 postbiotic cleared S. aureus. Keratinocytes treated invitro with BGMK2-41 upregulated expression of antimicrobial response genes, of which DEFB4, ANG, and RNASE7 were also found upregulated in treated exvivo human skin together with CAMP exclusively upregulated exvivo. Furthermore, BGMK2-41 postbiotic treatment has a multifaceted impact on the wound healing process. Treatment of keratinocytes stimulated cell migration and the expression of tight junction proteins, while in exvivo human skin BGMK2-41 increased expression of anti-inflammatory cytokine IL-10, promoted re-epithelialization, and restored the epidermal barrier via upregulation of tight junction proteins. Together, this provides a potential therapeutic approach for persistent intracellular S. aureus infections.

Safety, Immunogenicity, and Effectiveness of Chinese-Made COVID-19 Vaccines in the Real World: An Interim Report of a Living Systematic Review.

Background: Several COVID-19 vaccines were developed and approved in China. Of these, the BIBB-CorV and CoronaVac inactivated whole-virion vaccines were widely distributed in China and developing countries. However, the performance of the two vaccines in the real world has not been summarized. Methods: A living systematic review based on findings from ongoing post-licensure studies was conducted, applying standardized algorithms. Articles published between 1 May 2020 and 31 May 2022 in English and Chinese were searched for in Medline, Embase, WanFang Data, medRxiv, bioRxiv, arXiv, SSRN, and Research Square, using SARS-CoV-2, COVID-19, and vaccine as the MeSH terms. Studies with estimates of safety, immunogenicity, and effectiveness from receiving the BIBB-CorV or CoronaVac vaccine that met the predefined screening criteria underwent a full-text review. The Joanna Briggs Institute's Critical Appraisal Checklist and the Cochrane risk of bias were used for assessment of the quality. A random-effects meta-regression model was applied to identify the potential impact factors on the vaccines' effectiveness. Results: In total, 32578 articles were identified, of these, 770 studies underwent a full-text review. Eventually, 213 studies were included. The pooled occurrence of solicited and unsolicited adverse events after any dose of either vaccine varied between 10% and 40%. The top five commonly reported rare adverse events were immunization stress-related responses (211 cases, 50.0%), cutaneous responses (43 cases, 10.2%), acute neurological syndrome (39 cases, 9.2%), anaphylaxis (17 cases, 4.0%), and acute stroke (16 cases, 3.8%). The majority (83.3%) recovered or were relieved within several days. The peak neutralization titers against the ancestral strain was found within 1 month after the completion of the primary series of either vaccine, with a GMT (geometric mean titer) of 43.7 (95% CI: 23.2-82.4), followed by a dramatic decrease within 3 months. At Month 12, the GMT was 4.1 (95% CI: 3.8-4.4). Homologous boosting could restore humoral immunity, while heterologous boosting elicited around sixfold higher neutralization titers in comparison with homologous boosting. The effectiveness of receiving either vaccine against death and severe disease was around 85% for both shortly after the primary series. At Month 12, the protection against death did not decline, while the protection against severe disease decreased to ~75%. Conclusions: Both the BIBP-CorV and CoronaVac inactivated vaccines are safe. Sustained vaccine effectiveness against death was determined 12 months after the primary series, although protection against severe disease decreased slightly over time. A booster dose could strengthen the waning effectiveness; however, the duration of the incremental effectiveness and the additional benefit provided by a heterologous booster need to be studied.

Reflectance spectroscopy: a non-invasive strategy to explore skin reactions to topical products.

Reflectance spectroscopy has emerged as a powerful analytical technique in the field of dermatology, offering a non-invasive strategy to assess several cutaneous properties and skin response to topical products. By analyzing reflected light across different wavelengths, reflectance spectroscopy allows the quantification of cutaneous parameters, such as erythema index and melanin content. Moreover, this analytical technique enables the monitoring of any changes in skin physiology facilitating the assessment of long-term effects of topical products as well as predicting cutaneous diseases. This review provides an overview of the application of reflectance spectroscopy in investigating skin properties and reaction to topical applied products, including both pharmaceutical and cosmetic formulations, thereby aiding in the development of personalized solutions tailored to individual needs.

Microsponge: A Review

Microsponge are little spherical molecules with a broad porous surface that resemble sponges. The use of microsponges is a unique medication delivery method that has several benefits. For a range of illnesses, the Microsponges drug delivery system is utilized to improve the effectiveness of oral, parenteral, or topical medicine administration. A novel approach of managing drug release and administering medication to specific locations is microsponge technology. The efficient and novel way that microsponge medicine administration advances properties, boosts item stability, and improves security can all contribute to the effectiveness of topically dynamic operators. In an effective and creative way, it can boost the efficiency of topically active medications while improving safety, product stability, and aesthetic qualities. Recently, microsponges, which are typically used topically, have also been employed for oral delivery. Microsponge Systems may suspend or trap a wide range of substances. They can also be integrated into a product that is made to resemble a gel, cream, liquid, or powder. Microsponge Systems are built on atomic, polymer-based microspheres. In topical medication solutions, microsponge technology has been employed to provide controlled release of active drug into the skin, therefore decreasing systemic exposure and local cutaneous responses to active pharmaceuticals. We will talk about microsponge's characteristics, benefits, and drawbacks as well as the drug release mechanism, formulation techniques, and assessment in this review paper. Keywords: Microsponge, NDDS, Novel drug delivery system, MDS

Skin Manifestations of VEXAS Syndrome and Associated Genotypes

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations. To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features. This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland. To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS. Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]). Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.

Cutaneous Ulcers and Response to Treatment in a Child with Anti-MDA5 Dermatomyositis.

Cutaneous Ulcers and Response to Treatment in a Child with Anti-MDA5 Dermatomyositis.

Comparison of Intralesional Triamcinolone Acetonide Alone with Intralesional Triamcinolone Acetonide-5-Fluorouracil Combination Injection in Keloid: A Case Report

Keloids are abnormal cutaneous wound healing responses extending beyond the borders of the initial wound, usually appearing pink-purplish to hyperpigmented nodules or plaques with a hard consistency, irregular shape, uneven border, and smooth shiny surface. Most often occur on the chest, shoulder, upper arms, earlobes, and cheeks. This case report aims to compare a case of keloid treated with intralesional triamcinolone acetonide (TAC) alone with intralesional triamcinolone acetonide-5-fluorouracil (TAC + 5-FU) combination injection. A 21-year-old Minahasa male complains of growing pruritic scars in the back area and right and left upper arms since five years ago. Physical examination of the right and left upper arms revealed multiple hyperpigmented nodules and plaques, irregularly shaped, smooth, and shiny surfaces with defined borders and varying sizes. A clinical diagnosis of keloid was made. Treatment was initiated with weekly intralesional TAC alone on the left upper arm vs. intralesional TAC + 5-FU combination injection on the right upper arm. The evaluation was made based on the clinical and modified Vancouver scar scale. One of the most commonly used therapeutic options for keloid is TAC. However, the combination of TAC + 5-FU may be opted for due to its mechanism through the corticosteroid mechanism of action in conjunction with the antimetabolite activity of 5-FU. The combination may yield a more effective and faster outcome with fewer side effects. Intralesional combination TAC + 5-FU injection may be a therapeutic option for keloid with minimal side effects.

Evaluation of the inflammatory parameters as potential biomarkers of systemic inflammation extent and the disease severity in psoriasis patients.

The disease severity of psoriasis is mainly assessed subjectively via psoriasis area and severity index (PASI) and body surface area (BSA), while an optimal measure of cutaneous response, may overlook systemic inflammation in psoriasis patients. The neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), monocyte to high density lipoprotein ratio (MHR), and systemic immune-inflammation index (SII) exhibit notable associations with the inflammation severity in multiple diseases. The aim of this retrospective study was to explore the associations between inflammatory parameters and the skin lesions' severity of psoriasis. After analysis, we found that patients with psoriasis had higher NLR, MLR, PLR, MHR, and SII levels compared to the control group. At baseline, the parameters of NLR (r = 0.124, P = 0.003), MLR (r = 0.153, P < 0.001), MHR (r = 0.217, P < 0.001) and SII (r = 0.141, P = 0.001) had a positive correlation with PASI in psoriasis patients. At the same time, we analyzed thepatients who received different systemic therapy. We observed a significant decrease in NLR, PLR, MLR, and SII in psoriasis patients after treatment. Notably, TNF-α inhibitors and IL-17A inhibitors subgroups showed amore significant reduction than IL-23/IL-12/23 inhibitors and MTX medication. Additionally, we found the change of NLR (r = 0.194, P < 0.001), PLR (r = 0.104, P = 0.014), MLR (r = 0.191, P < 0.001), MHR (r = 0.106, P = 0.012), and SII (r = 0.228, P < 0.001) had a positive correlation with the change of PASI in psoriasis patients. In conclusion, this study suggests that NLR, MLR, and SII may serve as useful biomarkers for assessing systemic inflammation extent and disease severity in psoriasis patients.

The Dynamic Relationship between Dengue Virus and the Human Cutaneous Innate Immune Response.

Dengue virus (DENV) is a continuing global threat that puts half of the world's population at risk for infection. This mosquito-transmitted virus is endemic in over 100 countries. When a mosquito takes a bloodmeal, virus is deposited into the epidermal and dermal layers of human skin, infecting a variety of permissive cells, including keratinocytes, Langerhans cells, macrophages, dermal dendritic cells, fibroblasts, and mast cells. In response to infection, the skin deploys an array of defense mechanisms to inhibit viral replication and prevent dissemination. Antimicrobial peptides, pattern recognition receptors, and cytokines induce a signaling cascade to increase transcription and translation of pro-inflammatory and antiviral genes. Paradoxically, this inflammatory environment recruits skin-resident mononuclear cells that become infected and migrate out of the skin, spreading virus throughout the host. The details of the viral-host interactions in the cutaneous microenvironment remain unclear, partly due to the limited body of research focusing on DENV in human skin. This review will summarize the functional role of human skin, the cutaneous innate immune response to DENV, the contribution of the arthropod vector, and the models used to study DENV interactions in the cutaneous environment.

AMYLOID-BETA 40 ADVERSELY INFLUENCES LARGE ARTERY STIFFNESS AND CUTANEOUS MICROVASCULAR FUNCTION IN OLDER ADULTS WITH DIVERSE CARDIOVASCULAR RISK

Objective: Amyloid-beta (Aβ) peptides are considered to play a prominent role in Alzheimer's disease, but emerging experimental and clinical observations link Aβ40 with adverse extracerebral vascular manifestations and cardiovascular disease events. However, it is unclear if Aβ40 adversely influences both large artery stiffness and cutaneous microvascular function in humans. We sought to determine whether Aβ40 was associated with large artery stiffness and cutaneous microvascular function in older adults with diverse cardiovascular risk. Design and method: This cross-sectional study analysed data from 610 older adults (65.7±8.7 yrs, 242F). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (CFPWV) using a SphygmoCor device, and cutaneous microvascular function was assessed by measuring acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) responses following iontophoresis. Plasma Aβ40 concentration was measured using a human Aβ40 assay kit (Simoa Human A β40). Results: One standard deviation increase in Aβ40 was significantly associated with 0.74 (0.52, 0.96) m/s greater CFPWV in an age- and sex-adjusted model (Model-1, p&lt;0.001), which remained significant after further adjustments for conventional cardiovascular disease risk factors [Model-2, 0.46 (0.26, 0.66) m/s, p&lt;0.001]. Additionally, one standard deviation increase in Aβ40 was significantly associated with lower cutaneous acetylcholine [-27.3 (-38.9, -15.7) au] and sodium nitroprusside [-27.0 (-38.1, -15.9) au] responses in Model-1 (both p&lt;0.001). Further adjustments for conventional cardiovascular disease risk factors did not modify the inverse association [Model-2, acetylcholine response, -20.7 (-32.5, -8.8) au: sodium nitroprusside response, -21.1 (-32.3, -9.9) au: both p&lt;0.001]. Subgroup analyses found an indication of interaction effect whereby female sex influenced more on the association between Aβ40 and CFPWV, and type 2 diabetes influenced more on the association between Aβ40 and cutaneous acetylcholine responses (both p&lt;0.05). Conclusions: Aβ40 was associated with increased large artery stiffness and decreased cutaneous microvascular function in older adults with diverse cardiovascular risk. These findings suggest a potential mechanistic link between Aβ40 deposition in the systemic circulation and previously observed adverse cardiovascular disease outcomes.

Insulin-Mediated Capillary Recruitment Is Absent in the Cutaneous Microvasculature of Women with a History of Gestational Diabetes Mellitus

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater risk of developing cardiovascular disease and type II diabetes compared to women who had an uncomplicated pregnancy (HC). Although the mechanisms underlying this increased risk are unclear, emerging evidence suggests that microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation, persists after pregnancy complicated by GDM. Whether this microvascular dysfunction reduces insulin-mediated responses in these women is unexplored. We hypothesized that insulin-mediated capillary recruitment would be attenuated in women with a history of GDM via NO-dependent mechanisms. 24 women (n=12/group; HC: 35±1 years, 24±4 months post-partum; GDM: 33±1 years, 21±3 months postpartum) underwent intradermal microdialysis, which involved the placement of 2 fibers in the ventral forearm for the local delivery of 10−4M insulin alone or 10−4M insulin+15mM NG-nitro-L-arginine methyl ester (L-NAME, NO-synthase inhibitor). The cutaneous blood flow response to post-occlusive reactive hyperemia (PORH; 5 minutes) was assessed before and during insulin perfusion. Red blood cell flux was measured continuously over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure), normalized to maximum (%CVCmax), and presented as PORH area under the curve (AUC, %CVCmax• sec−1). Microvascular capillary recruitment was assessed as ΔAUC (pre-insulin AUC - insulin AUC). Insulin perfusion increased PORH in HC (pre-insulin: 4066±490 vs. insulin: 7848±978 AUC; p=0.03) but had no effect in GDM (pre-insulin: 3765±293 vs. insulin: 6196±779 AUC; p=0.26). Insulin perfusion did not increase PORH at the L-NAME site in either group (p&gt;0.05). Within groups, L-NAME perfusion reduced insulin-mediated capillary recruitment in HC (control: 3781±1109 vs. L-NAME: 470±945 ΔAUC; p=0.04) but not GDM (control: 2431±796 vs. L-NAME: -41±1014 ΔAUC, p=0.11). These data suggest that insulin-mediated capillary recruitment assessed by PORH in the cutaneous circulation is mediated by NO-dependent mechanisms in healthy women with a history of uncomplicated pregnancy and attenuated in healthy women with a history of GDM. This reduction in insulin-mediated microvascular responses may contribute to the increased risk of cardiovascular disease and type II diabetes in these women. UI Fraternal Order of Eagles Diabetes Research Center Catalyst Grant; NIH HL169201. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Divergent Vasodilator Mechanisms to Endothelial-Dependent Agonists with Advancing Age

Introduction: Microvascular function is maintained by a number of vasodilating factors, with nitric oxide (NO) and endothelial hyperpolarizing factors (EDHF) predominating. Advancing age is an independent risk factor in the development of cardiovascular disease, and NO-mediated vasodilation declines, or is unchanged, depending on the vascular bed examined, number of cardiovascular risk factors, or specific endothelial-dependent agonist used. Mechanisms contributing to cutaneous microvascular dysfunction with age have been attributed largely to reductions in NO signaling, but the role of EDHF-mediated dilation, particularly to acetylcholine (ACh), remains unclear. The purpose of this study was to determine the endothelial mechanisms contributing to age-induced cutaneous microvascular function and compare cutaneous microvascular function responses to those from isolated adipose arteriole preparations. We hypothesized that cutaneous microvascular vasodilation to ACh in older adults will be mediated primarily by EDHFs relative to young adults and that isolated adipose arteriole preparations will corroborate these findings. Methods: Four intradermal microdialysis fibers were placed in the skin of the ventral forearm of 9 young (3F/6M; 29±7 yrs) and 3 older adults (3F/0M; 59±11 yrs) for infusion of Ringer’s solution; L-NAME (10 mM), an NO synthase inhibitor; tetraethylammonium chloride (TEA; 50 mM), a non-specific K+ channel inhibitor; and a combination of L-NAME and TEA. Laser Doppler flowmetry and brachial mean arterial pressure were measured during infusion of ACh (10 mM and 100 mM) and in response to local heating to 39°C. Maximal vasodilation was assessed with heating to 43°C and infusion of sodium nitroprusside (28 mM). Adipose resistance arterioles for pressure myography were obtained from a gluteal biopsy or from surgical discard tissue, which were pre-constricted (ET-1), and ACh responses (10−9–10−4 M) were assessed in the presence of the above inhibitors. Cutaneous vascular conductance (CVC) and isolated arteriole responses are presented as % maximum vasodilation. Results: In response to local heating in young adults, L-NAME reduced vasodilator magnitude (Ringers 69.0±18.1% vs. L-NAME 30.3±12.1%; p&lt; 0.05) while TEA did not have any effect (69±18% vs. 49±28%; p=0.20). Combined L-NAME and TEA reduced vasodilation (69±18% vs. 19±6%; p&lt;0.05). Conversely, vasodilator magnitude to ACh was not different across the Ringers, L-NAME, or TEA sites (p=0.93-0.94), while combined inhibition of NOS and K+ channels with L-NAME and TEA, respectively, reduced vasodilator responsiveness (p&lt;0.05). In isolated resistance arterioles, there were no differences in %max dilation to ACh across inhibitor sites (p=0.19) in young adults. In older adults, neither independent nor combined inhibition of NOS or K+ channels impacted vasodilator responses to local heating, while vasodilator magnitude to ACh was most impacted by combined inhibition with L-NAME and TEA (83±14% vs. 32±15%; p&lt;0.05). Conclusion: Our data demonstrate that vasodilator plasticity in response to local heating is divergent with advancing age, relying on non-NO or K+ mechanisms relative to young adults, while NO and K+ mechanisms are suffcient to maintain ACh-mediated vasodilation. These findings further support the concept of diversity in vasodilator mechanisms within the microvasculature. NHLBI K99-HL161491 (WEH), K08-HL150340 (JJM), R01-HL160752 (JKF), R01-HL133029 (AB), and NICHD R01-HD099340 (MJD). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.