Mouse Model Of Dermatitis Research Articles

Increased Mortality Risk at Septic Condition in Inflammatory Skin Disorders and the Effect of High-Fat Diet Consumption.

In recent years, attention has increasingly focused on various infectious diseases. Although some fatalities are directly attributed to the causative virus, many result from complications and reactive inflammation. Patients with comorbidities are at a higher risk of mortality. Refractory skin conditions such as atopic dermatitis, psoriasis, and epidermolysis bullosa, known for an elevated risk of sepsis, partly owe this to compromised surface barrier function. However, the detailed mechanisms underlying this phenomenon remain elusive. Conversely, although the detrimental effects of a high-fat diet on health, including the onset of metabolic syndrome, are widely recognized, the association between diet and susceptibility to sepsis has not been extensively explored. In this study, we examined the potential causes and pathogenesis of increased sepsis susceptibility in inflammatory skin diseases using a mouse dermatitis model: keratin 14-driven caspase-1 is overexpressed (KCASP1Tg) in mice on a high-fat diet. Our findings reveal that heightened mortality in the dermatitis mouse model is caused by the inflamed immune system due to the chronic inflammatory state of the local skin, and administration of LPS causes a rapid increase in inflammatory cytokine levels in the spleen. Intake of a high-fat diet exacerbates these cytokine levels. Interestingly, we also observed a reduced expression of Toll-like receptor 4 (TLR4) in monocytes from KCASP1Tg mice, potentially predisposing these animals to heightened infection risks and associated complications. Histological analysis showed a clear decrease in T and B cells in the spleen of KCASP1Tg mice fed a high-fat diet. Thickening of the alveolar wall, inflammatory cell infiltration, and alveolar hemorrhage were more prominent in the lungs of KCASP1Tg and KCASP1Tg with fat mice. We postulate that the chronic, non-infectious inflammation induces a negative feedback loop within the inflammatory cascade, and the suppressed expression of TLR4 renders the mice more susceptible to infections. Therefore, it is imperative for individuals with chronic skin inflammation to closely monitor disease progression upon infection and seek timely and appropriate treatment. Additionally, chronic inflammation of adipose tissue, induced by high-fat food intake, combined with dermatitis inflammation, may exacerbate infections, necessitating a review of dietary habits.

Characterization of Different Inflammatory Skin Conditions in a Mouse Model of DNCB-Induced Atopic Dermatitis

The mouse model of 2,4-dinitrochlorbenzene (DNCB)-induced human-like atopic dermatitis (hlAD) has been widely used to test novel treatment strategies and compounds. However, the study designs and methods are highly diverse, presenting different hlAD disease patterns that occur after sensitization and repeated challenge with DNCB on dorsal skin. In addition, there is a lack of information about the progression of the disease during the experiment and the achieved pheno- and endotypes, especially at the timepoint when therapeutic treatment is initiated. We here examine hlAD in a DNCB-induced BALB/cJRj model at different timepoints: (i) before starting treatment with dexamethasone, representing a standard drug control (day 12) and (ii) at the end of the experiment (day 22). Both timepoints display typical AD-associated characteristics: skin thickening, spongiosis, hyper- and parakeratosis, altered cytokine and gene expression, increased lipid mediator formation, barrier protein and antimicrobial peptide abnormalities, as well as lymphoid organ hypertrophy. Increased mast cell infiltration into the skin and elevated immunoglobulin E plasma concentrations indicate a type I allergy response. The DNCB-treated skin showed an extrinsic moderate sub-acute hlAD lesion at day 12 and an extrinsic mild sub-acute to chronic pheno- and endotype at day 22 with a dominating Th2 response. A dependency of the filaggrin formation and expression in correlation to the disease severity in the DNCB-treated skin was found. In conclusion, our study reveals a detailed classification of a hlAD at two timepoints with different inflammatory skin conditions and pheno- and endotypes, thereby providing a better understanding of the DNCB-induced hlAD model in BALB/cJRj mice.

A Comparative Study to Examine the Effects of Topical Vinpocetine and Tacrolimus on Induced Atopic Dermatitis in Mice.

Background: Atopic dermatitis (AD) is a persistent and recurring inflammatory skin disorder distinguished by parched skin and severe itching. The pathogenesis of AD involves increased production of specific cytokines, such as Interlukin-4 (IL-4) and Interlukin-13 (IL-13), which are associated with the T helper 2 pathway. However, prolonged use of the current glucocorticoids and calcineurin inhibitors medications can lead to adverse effects. Aim of the study: To assess the efficiency of topical Vinpocetine and Tacrolimus in treating an induced atopic dermatitis mice model. Methods: Five sets of fifty male Albino mice, were randomly selected. One-chloro-2,4-dinitrobenzene (DNCB) was applied to the dorsal (back) skin of forty mice to cause atopic dermatitis. Ten control healthy mice were placed in Group I, ten mice with atopic dermatitis were placed in Group II; neither group received any treatment. Group III consists of 10 mice that received tacrolimus 0.1% ointment, group IV was administered a topical ointment comprising 5% Vinpocetine and lastly, group V underwent a vehicle ointment. Severity was assessed visually, IL-4 and IL-13 were measured by immunohistochemistry, in addition to general histopathological evaluation as well as examining WBCs. Results: The groups treated with Vinpocetine 5%, and Tacrolimus all had significantly lower levels of WBC counts, decreased IL-4 and IL-13 staining according to immunohistochemistry and lower histopathological scores. Vinpocetine 5% and tacrolimus treatment also showed a statistically significant reduction in hyperkeratosis and inflammation among the studied groups (P<0.001). Conclusions Topical Vinpocetine 5% ointment, and tacrolimus 0.1% were effective in the treatment of induced AD mouse model through the improvement of histopathological changes and their ability to decrease IL-4 and IL-13, Vinpocetine were effective in the treatment of induced AD. Keywords: Atopic dermatitis, Tacrolimus, Topical, Vinpocetine.

Therapeutic effects and mechanism of action of lavender essential oil on atopic dermatitis by modulating the STAT3/RORγt pathway

ObjectivesAtopic dermatitis (AD) is a common skin disorder characterized by skin inflammation caused by an imbalance in the immune response. The efficacy of lavender essential oil in treating atopic dermatitis has been demonstrated; however, its specific mechanism of action and active components remain unknown. Therefore, this study investigated the therapeutic effects and possible mechanism of action of LEO on AD in a 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis mice model. MethodsTo determine the efficacy of LEO, serum levels of the cytokines IL-6 and TNF-α were tested in Kunming mice, and network pharmacology was used to predict the targets and mechanisms of LEO in AD treatment, after which network pharmacology was combined with metabolomics to construct complex response–enzyme–gene networks and investigate their potential associations. Based on the predicted mechanisms, skin tissues were further examined by immunohistochemistry and immunoblotting analysis, and the skin epidermis was stained with hematoxylin-eosin (HE) and toluidine blue (TB). ResultsLEO significantly suppressed the basal levels of IL-6 and TNF-α in the DNCB-induced mice model and predicted that Th17 cell differentiation is a critical pathway for LEO-based network pharmacology in AD treatment. As for the cytokines associated with the Th17 cell differentiation pathway, further experiments verified that LEO significantly reduced the protein expression of interleukin-17A (IL-17A)、Phosphorylated JAK2 (p-JAK)、Phosphorylated STAT3 (p-STAT3), and Retinoic acid-related orphan receptor γt (RORγt) but increased the expression of Foxp3. Additionally, the results of combined network pharmacology and metabolomics analysis showed that LEO could improve two metabolic pathways, namely, linoleic acid metabolism and arachidonic acid metabolism, by regulating the Th17 cell differentiation pathway; identify two key metabolites (linoleic acid, arachidonic acid); and regulate two differential genes (PTGS1, HPGD). ConclusionLEO may alleviate DNCB-induced skin inflammation by inhibiting the STAT3/RORγt pathway in Th17 cell differentiation, and reducing the expression of associated inflammatory cytokines and chemokines and improving the metabolism of linoleic and arachidonic acid in vivo.

Synthesis of 9-Cinnamyl-9H-purine Derivatives as Novel TLR4/MyD88/NF-κB Pathway Inhibitors for Anti-inflammatory Effects.

The novel 9-cinnamyl-9H-purine skeleton, inspired by resveratrol and curcumin, was developed to avoid a pan-assay interference compound (PAINS) related to invalid metabolic pancreas activity (IMPS). It replaced the phenol group with purine analogues, the building blocks of DNA and RNA. Alterations to the hydroxyl group in the cinnamyl group, such as H, Me, or F substitutions, were made to impede its oxidation to a PAINS-associated quinone. Among the compounds tested, 5e significantly inhibited nitric oxide production in LPS-induced macrophages (IC50: 6.4 vs 26.4 μM for resveratrol). 5e also reduced pro-inflammatory cytokine levels (IL-6, TNF-α, IL-1β) and lowered iNOS and COX-2 protein levels. Mechanistically, 5e disrupted the TLR4-MyD88 protein interaction, leading to the suppression of the NF-κB signaling pathway suppression. In an atopic dermatitis mouse model, 5e reduced ear edema and inflammation. These findings indicate that the novel 9-cinnamyl-9H-purine skeleton provides therapeutic insight into treating various human diseases by regulating inflammation.

Toxin metalloproteinases exert a dominant influence on pro-inflammatory response and anti-inflammatory regulation in jellyfish sting dermatitis

Toxin metalloproteinases are the primary components responsible for various toxicities in jellyfish venom, and there is still no effective specific therapy for jellyfish stings. The comprehension of the pathogenic mechanisms underlying toxin metalloproteinases necessitates further refinement. In this study, we conducted a differential analysis of a dermatitis mouse model induced by jellyfish Nemopilema nomurai venom (NnNV) samples with varying levels of metalloproteinase activity. Through skin tissue proteomics and serum metabolomics, the predominant influence of toxin metalloproteinase activity on inflammatory response was revealed, and the signal pathway involved in its regulation was identified. In skin tissues, many membrane proteins were significantly down-regulated, which might cause tissue damage. The expression of pro-inflammatory factors was mainly regulated by PI3K-Akt signaling pathway. In serum, many fatty acid metabolites were significantly down-regulated, which might be the anti-inflammation feedback regulated by NF-κB p65 signaling pathway. These results reveal the dermatitis mechanism of toxin metalloproteinases and provide new therapeutic targets for further studies. SignificanceOmics is an important method to analyze the pathological mechanism and discover the key markers, which can reveal the pathological characteristics of jellyfish stings. Our research first analyzed the impact of toxin metalloproteinases on jellyfish sting dermatitis by skin proteomics and serum metabolomics. The present results suggest that inhibition of toxin metalloproteinases may be an effective treatment strategy, and provide new references for further jellyfish sting studies.

Ishige okamurae Extract: Diphlorethohydroxycarmalol with Effect of Atopic Dermatitis-Like Skin Inflammation

Ishigeokamurae Yendo 1907, Fucaceae, a brown alga, has garnered attention for its antipyretic, anti-inflammatory, and anti-edema properties. While numerous studies have explored the effects of a 95% ethanol extract of I. okamurae, limited research has been conducted on its 70% ethanol extract. This study focuses on diphlorethohydroxycarmalol, a bioactive compound identified in the 70% ethanol extract of I. okamurae. Diphlorethohydroxycarmalol has garnered significant interest due to its potential health benefits, including antioxidant, anti-inflammatory, antiviral, and anticancer properties. We investigate the impact of the 70% ethanol extract of I. okamurae and diphlorethohydroxycarmalol on atopic dermatitis using human keratinocyte cell lines (HaCaT) and atopic dermatitis mouse models induced by dinitrochlorobenzene and house dust mite. Treatment with extract of I. okamurae effectively reduced dinitrochlorobenzene/house dust mite -induced ear edema, ear thickness, mast cell infiltration, as well as levels of immunoglobulin (Ig) E, IgG1, IgG2a, cytokines, and chemokines in atopic dermatitis mice. In HaCaT cells, extract of I. okamurae also suppressed TNF-α/IFN-γ-induced cytokine and chemokine production. To further understand the anti-atopic and anti-inflammatory properties of extract of I. okamurae, we evaluated the effects of diphlorethohydroxycarmalol on atopic dermatitis mice and HaCaT cells. In atopic dermatitis mice, diphlorethohydroxycarmalol demonstrated the ability to reduce the inflammatory response induced by TNF-α/IFN-γ. These findings highlight the potential of extract of I. okamurae as an anti-inflammatory agent for inflammatory skin disorders and suggest that diphlorethohydroxycarmalol may represent a promising therapeutic approach for the treatment of inflammatory skin diseases.Graphical

The JAK/STAT/NF-κB signaling pathway can be regulated by rosemary essential oil, thereby providing a potential treatment for DNCB-induced in mice

ObjectiveThe purpose of this study was to investigate the mechanism through which rosemary essential oil treats atopic dermatitis. MethodsA dinitrochlorobenzene (DNCB)-induced atopic dermatitis mouse model was established and treated with low (1%), medium (2%), and high (4%) doses of Rosmarinus officinalis essential oil (EORO). Serum levels of interleukin (IL)−6 and tumor necrosis factor-alpha (TNF-α) in each group were determined using enzyme-linked immunosorbent assay (ELISA). Skin tissues were stained with hematoxylin-eosin and toluidine blue. We used network pharmacology and molecular docking techniques to verify the biological activity of essential proteins and their corresponding compounds in the pathway. Gas chromatography-mass spectrometry (GC-MS) was used for metabolomics analysis and multivariate statistical analysis of mouse serum to screen differential metabolites and metabolic pathway analysis. Protein expression of p-JAK1, CD4+ cells, and IL-4 in the skin tissue was detected by immunohistochemistry analysis. Protein levels of STAT3, p-STAT3, P65, and p-P65 in damaged skin tissues were detected using western blotting. ResultThe skin of mice in the model group showed different degrees of erythema, dryness, scratches, epidermal erosion and shedding, and crusting. After treatment, the serum levels of IL-6 and TNF-α in EORO group were significantly decreased, and the expression of p-JAK1,CD4 + cells, IL-4, p-P65 / P65 and p-STAT3 / STAT3 proteins in skin tissues were decreased. ConclusionEORO can effectively improve DNCB-induced AD-like skin lesions in mice by regulating the JAK/STAT/NF-κB signaling pathway, thereby reducing the production of downstream arachidonic acid metabolites, inhibiting skin inflammation, and restoring epidermal barrier function.

Anti-Inflammatory and Antipruritic Effects of Remote Ischaemic Postconditioning in a Mouse Model of Experimental Allergic Contact Dermatitis.

Background and Objectives: Allergic contact dermatitis is a common type IV hypersensitivity reaction characterised by redness, itching, oedema and thickening of the skin. It occurs in about 7% of the population and its incidence is increasing. It has been observed that the preconditioning of tissues by exposing them to transient ischemia increases resistance to subsequent permanent ischemia, and this phenomenon is called ischemic preconditioning. It has been shown that conditioning in one organ can also protect other organs. The protective effect of remote ischemic preconditioning is thought to be based on the induction of anti-inflammatory responses. The aim of this project was to investigate the anti-inflammatory and antipruritic effects of remote ischemic postconditioning in a mouse model of experimental allergic contact dermatitis. Methods: Experimental allergic contact dermatitis was induced with 1-fluoro-2,4-dinitrobenzene. Remote ischemic postconditioning was performed at 3 and 25 h after the challenge. Ear thickness and number of scratches 24 and 48 h after challenge, as well as cytokine levels and the infiltration of mast cells, neutrophils, CD4+ and CD8+ T lymphocytes in serum and ear tissue at 48 h were measured to determine the effect of RIPsC. Results: Remote ischemic postconditioning decreased ear thickness, one of the symptoms of allergic contact dermatitis (p < 0.0001). It had no significant effect on the number of scratches. It reduced serum IL-17 levels (p < 0.01). It alleviated local inflammation by suppressing CD8+ T lymphocyte and neutrophil infiltration. Conclusions: It was concluded that remote ischemic postconditioning may alleviate the symptoms of allergic contact dermatitis by suppressing CD8+ T lymphocyte and neutrophil infiltration and reducing IL-17 secretion.

Attenuated effects of topical vinpocetine in an imiquimod-induced mouse model of psoriasis

Psoriasis is an uncontrolled, long-lasting inflammatory dermatosis distinguished by thickened, erythematous, and flaky skin lesions. Massive amounts of inflammatory cytokines are produced when immune system imbalances are driven by genetic and environmental triggers. Vinpocetine (VNP), a man-made analogue of the compound vincamine found in the dwarf periwinkle herb, has robust anti-inflammatory, immunomodulatory, and anti-oxidative effects; alleviates the epidermal penetration of immune cells, such as eosinophils and neutrophils; and abolishes the generation of pro-inflammatory molecules. ObjectiveThis study was aimed at exploring the effects of long-term topical VNP, both alone and co-administered with clobetasol propionate, in an imiquimod-induced mouse model of psoriasiform dermatitis. MethodsThe study protocol consisted of 48 Swiss albino mice, randomly divided into six groups of eight mice each. In group I, petroleum jelly was administered daily for 8 days. In group II, imiquimod was administered topically at 62.5 mg daily for 8 days. In groups III, VI, V, and VI, 0.05% clobetasol propionate, 1% VNP, 3% VNP, and 3% VNP plus 0.05% clobetasol were administered topically for an additional 8 days after the induction, thus resulting in a total trial length of 16 days. ResultsTopical VNP at various doses alleviated the severity of imiquimod-induced psoriatic lesions—including erythema, silvery-white scaling, and thickening—and reversed the histopathological abnormalities. Moreover, imiquimod-exposed animals treated with VNP showed markedly diminished concentrations of inflammatory biomarkers, including tumour necrosis factor-α, interleukin (IL)-8, IL-17A, IL-23, IL-37, nuclear factor-kappa B (NF-κB), and transforming growth factor-β1. ConclusionThis research provides new evidence that VNP, alone and in combination with clobetasol, may serve as a potential adjuvant for long-term management of autoimmune and autoinflammatory skin diseases, particularly psoriasis, by attenuating psoriatic lesion severity, suppressing cytokine generation, and limiting NF-κB-mediated inflammation.

Age-Related Skin Inflammation in A 2,4-Dintrochlorobenzene-Induced Atopic Dermatitis Mouse Model.

One of the most affected aspects of the aging process is immunity, with age-related immune system decline being responsible for an increase in susceptibility to infectious diseases and cancer risk. On the other hand, the aging process is accompanied with low-grade pro-inflammatory status. This condition involves a persistent rise in cytokine levels that can activate both innate and adaptive immune systems. Finally, despite the fact that immunological responses to antigenic stimulations decrease with age, the incidence and prevalence of many common autoimmune diseases increase in the elderly population. Overall, the co-existence of a prolonged, low-grade inflammatory status and declining immune activity appears to be a paradoxical phenomenon. This study characterized skin inflammation in mouse dermatitis model of various ages to monitor possible changes of inflammatory responses during aging.

Crisaborole Inhibits Itch and Pain by Preventing Neutrophil Infiltration in a Mouse Model of Atopic Dermatitis.

Crisaborole, a phosphodiesterase 4 (PDE4) inhibitor, has been approved for the treatment of mild to moderate atopic dermatitis. Atopic dermatitis is often associated with increased pain. Using a mouse model, this study investigated whether crisaborole suppresses pain associated with atopic dermatitis and the potential mechanisms underlying it. The mouse model for atopic dermatitis was developed by repeatedly applying MC903. MC903-treated mice had increased spontaneous scratching (itch-related behaviour) and wiping behaviour (pain-related behaviour). Crisaborole was topically applied to the cheek skin of MC903-treated mice, and it reduced both itch- and pain-related behaviours in these mice. Immunofluorescence staining revealed that crisaborole reduced neutrophil infiltration and interaction of neutrophils with sensory neurones. Intradermal injection of S100A8/A9, proinflammatory neutrophil mediator, enhanced not only itch-related behaviours evoked by histamine or chloroquine, but also pain-related behaviours evoked by capsaicin. Calcium imaging of mouse dorsal root ganglion neurones revealed that pretreatment with S100A8/A9 significantly increased calcium responses to histamine and capsaicin, and the proportion of chloroquine-sensitive neurones. These findings suggest that the PDE4 inhibitor reduces itch and pain, in part by inhibiting infiltration of S100A8/A9-containing neutrophils in a mouse model of MC903-induced atopic dermatitis.

Inflammatory and Immunomodulatory Effects of Tripterygium wilfordii Multiglycoside in Mouse Models of Psoriasis Keratinocytes.

To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ+TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45+ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.

Chronic oral exposure to low-concentration fumonisin B2 significantly exacerbates the inflammatory responses of allergies in mice via inhibition of IL-10 release by regulatory T cells in gut-associated lymphoid tissue.

Contamination with fumonisins produced by Fusarium spp. is rapidly growing in both developing and developed countries. The purpose of this study was to determine whether oral exposure to fumonisin contributed to the development of allergic diseases. We initially examined the immunotoxic potential of short-term, oral administration of fumonisin B1 (FB1, 1mg/kg) and fumonisin B2 (FB2, 1mg/kg), both naturally occurring fumonisins, using a BALB/c mouse model of allergic contact dermatitis and Dermatophagoides farina-induced asthma. Using an NC/nga mouse model of atopic dermatitis (AD), we evaluated the adverse effects of subchronic oral exposure to low concentrations of FB2 (2 or 200μg/kg). Finally, we explored the influence of FB2 on regulatory T cell proliferation and function in mesenteric lymph nodes after 1-week oral exposure to FB2 in BALB/c mice. Oral exposure to FB2 markedly exacerbated the symptoms of allergy, including skin thickness, histological evaluation, immunocyte proliferation, and proinflammatory cytokine production, although no change was observed following exposure to FB1. Furthermore, oral exposure to low concentrations of FB2 considerably exacerbated the AD scores, skin thickness, transepidermal water loss, histological features, and proinflammatory cytokine production. The aggravated allergic symptoms induced by oral exposure to FB2 could be attributed to the direct inhibition of IL-10 production by regulatory T cells in mesenteric lymph nodes. Our findings indicate that the recommended maximum fumonisin level should be reconsidered based on the potential for allergy development.

Forward genetics and functional analysis highlight Itga11 as a modulator of murine psoriasiform dermatitis.

Psoriasis is a chronic inflammatory skin condition. Repeated epicutaneous application of Aldara® (imiquimod) cream results in psoriasiform dermatitis in mice. The Aldara®-induced psoriasiform dermatitis (AIPD) mouse model has been used to examine the pathogenesis of psoriasis. Here, we used a forward genetics approach in which we compared AIPD that developed in 13 different inbred mouse strains to identify genes and pathways that modulated disease severity. Among our primary results, we found that the severity of AIPD differed substantially between different strains of inbred mice and that these variations were associated with polymorphisms in Itga11. The Itga11 gene encodes the integrin α11 subunit that heterodimerizes with the integrin β1 subunit to form integrin α11β1. Less information is available about the function of ITGA11 in skin inflammation; however, a role in the regulation of cutaneous wound healing, specifically the development of dermal fibrosis, has been described. Experiments performed with Itga11 gene-deleted (Itga11-/- ) mice revealed that the integrin α11 subunit contributes substantially to the clinical phenotype as well as the histopathological and molecular findings associated with skin inflammation characteristic of AIPD. Although the skin transcriptomes of Itga11-/- and WT mice do not differ from one another under physiological conditions, distinct transcriptomes emerge in these strains in response to the induction of AIPD. Most of the differentially expressed genes contributed to extracellular matrix organization, immune system, and metabolism of lipids pathways. Consistent with these findings, we detected a reduced number of fibroblasts and inflammatory cells, including macrophages, T cells, and tissue-resident memory T cells in skin samples from Itga11-/- mice in response to AIPD induction. Collectively, our results reveal that Itga11 plays a critical role in promoting skin inflammation in AIPD and thus might be targeted for the development of novel therapeutics for psoriasiform skin conditions. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

IL-22–Induced Ubiquitin-Specific Protease 15 Promotes Proliferation and Inflammation of Keratinocytes through Stabilization of Squamous Cell Carcinoma Antigen 2

Ubiquitin-specific protease 15 (USP15) plays a significant role in regulating various biological processes in several autoimmune diseases and cancers. However, its role in psoriatic keratinocytes (KCs) has not been extensively studied. In this study, we described that USP15 promotes proliferation and inflammation in KCs by stabilizing squamous cell carcinoma antigen 2. We discovered that the expression of USP15 and squamous cell carcinoma antigen 2 was elevated in lesions from patients with clinical psoriasis and an imiquimod-induced psoriatic dermatitis mouse model. USP15 was able to bind, deubiquitinate, and stabilize squamous cell carcinoma antigen 2. Knocking down USP15 resulted in reduced KC inflammation and impaired KC viability and clonogenicity. Topically applying USP15 small interfering RNA significantly ameliorated imiquimod-induced psoriatic dermatitis and reduced the infiltration of T cells and neutrophils. In addition, we determined that IL-22 was a key cytokine that upregulated the expression of USP15. These findings provide insights regarding the mechanisms involved in the proliferation and inflammation of KCs mediated by IL-22, suggesting a potential IL-22-USP15-squamous cell carcinoma antigen 2 axis in the pathogenesis of psoriatic KCs.

Chitinase-3-like 1 regulates TH2 cells, TFH cells and IgE responses to helminth infection.

Data from patient cohorts and mouse models of atopic dermatitis, food allergy and asthma strongly support a role for chitinase-3-like-1 protein (CHI3L1) in allergic disease. To address whether Chi3l1 also contributes to TH2 responses following nematode infection, we infected Chi3l1 -/- mice with Heligmosomoides polygyrus (Hp) and analyzed T cell responses. As anticipated, we observed impaired TH2 responses in Hp-infected Chi3l1 -/- mice. However, we also found that T cell intrinsic expression of Chi3l1 was required for ICOS upregulation following activation of naïve CD4 T cells and was necessary for the development of the IL-4+ TFH subset, which supports germinal center B cell reactions and IgE responses. We also observed roles for Chi3l1 in TFH, germinal center B cell, and IgE responses to alum-adjuvanted vaccination. While Chi3l1 was critical for IgE humoral responses it was not required for vaccine or infection-induced IgG1 responses. These results suggest that Chi3l1 modulates IgE responses, which are known to be highly dependent on IL-4-producing TFH cells.

Importance of PLD2 in an IL-23 driven psoriasiform dermatitis model and potential link to human psoriasis.

Phospholipase D2 (PLD2), a major isoform of the PLD family, has been reported to regulate inflammatory responses. Thus far, the relevance of PLD2 in psoriasis, an inflammatory skin disease, has not been explored. In the current study, we examined PLD2 expression in the skin of psoriasis patients and the role of PLD2 in an interleukin (IL)-23-induced mouse model of psoriasiform dermatitis. Both in situ hybridization and bulk RNA sequencing showed PLD2 gene expression is significantly higher in lesional relative to non-lesional skin of psoriasis patients or the skin of healthy subjects. PLD2 expression is also enriched in residual lesions from patients on biologic therapies. Murine in vivo studies showed that PLD2 deficiency significantly reduced psoriasiform inflammation in IL-23-injected ears, as reflected by decreases in ear thickness, expression of defensin beta 4A and the S100 calcium binding protein A7A, macrophage infiltrate, and expression of CXCL10 and IL-6. However, the expression of type 17 cytokines, IL-17A and IL-17F, were not reduced. Dual knockout of PLD1 and PLD2 offered little additional protection compared to PLD2 knockout alone in the IL-23 model. In addition, pharmacological inhibition with a pan-PLD1/PLD2 inhibitor also suppressed IL-23-induced psoriasiform dermatitis. Bone-marrow-derived macrophages from wild type (WT) and PLD2 knockout (KO) mice exhibited little difference in viability and sensitivity to lipopolysaccharide and/or interferon gamma, or resiquimod (R848). PLD2 deficiency did not alter the differentiation and function of Th17 cells in an ex vivo study with splenocytes isolated from WT and PLD2 KO mice. Overall, these data suggest that PLD2 may play a role in the pathophysiology of psoriasis. Reducing macrophage infiltrate and cytokine/chemokine production might contribute to an anti-inflammatory effect observed in PLD2 knockout mice. Further studies are required to better understand the mechanisms by which PLD2 contributes to skin lesions in psoriasis patients and psoriasiform dermatitis models.

IL-17A exacerbates psoriasis in a STAT3 overexpressing mouse model.

Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal transducers and activators of transcription 3 (STAT3) play a crucial role in linking activated keratinocytes and immunocytes during psoriasis development. T helper (Th) 17 cells and secreted interleukin (IL)-17A contribute to its pathogenesis. IL-17A treated STAT3 overexpressing mouse model might serve as an animal model for psoriasis. In this study, we established a mouse model of psoriasiform dermatitis by intradermal IL-17A injection in STAT3 overexpressing mice. Transcriptome analyses were performed on the skin of wild type (WT), STAT3, and IL-17A treated STAT3 mice. Bioinformatics-based functional enrichment analysis was conducted to predict biological pathways. Meanwhile, the morphological and pathological features of skin lesions were observed, and the DEGs were verified by qPCR. IL-17A treated STAT3 mice skin lesions displayed the pathological features of hyperkeratosis and parakeratosis. The DEGs between IL-17A treated STAT3 mice and WT mice were highly consistent with those observed in psoriasis patients, including S100A8, S100A9, Sprr2, and LCE. Gene ontology (GO) analysis of the core DEGs revealed a robust immune response, chemotaxis, and cornified envelope, et al. The major KEGG enrichment pathways included IL-17 and Toll-like receptor signaling pathways. IL-17A exacerbates psoriasis dermatitis in a STAT3 overexpressing mouse.

Jing-Fang powder ethyl acetate extracts attenuate atopic dermatitis by modulating T-cell activity

Jing-Fang powder ethyl acetate extract (JFEE) and its isolated C (JFEE-C) possess favorable anti-inflammatory and anti-allergic properties; however, their inhibitory effects on T cell activity remain unknown. In vitro, Jurkat T cells and primary mouse CD4+ T cells were used to explore the regulatory effects of JFEE and JFEE-C as well as their potential mechanisms on activated T cells. Furthermore, T cell-mediated atopic dermatitis (AD) mouse model was established to confirm these inhibitory effects in vivo. The results showed that JFEE and JFEE-C inhibited T cell activation by suppressing the production of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) without showing cytotoxicity. Flow cytometry showed the inhibitory effects of JFEE and JFEE-C on the activation-induced proliferation and apoptosis of T cells. Pretreatment with JFEE and JFEE-C also decreased the expression levels of several surface molecules, including CD69, CD25, and CD40L. Moreover, it was confirmed that JFEE and JFEE-C inhibited T cell activation by downregulating the TGF-β-activated kinase 1 (TAK1)/nuclear kappa-light-chain-enhancer of activated B cells (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathways. The combination of these extracts with C25–140 intensified the inhibitory effects on IL-2 production and p65 phosphorylation. The oral administration of JFEE and JFEE-C notably weakened AD manifestations, including the infiltration of mast cells and CD4+ cells, epidermis and dermis thicknesses, serum levels of immunoglobulin E (IgE) and thymic stromal lymphopoietin (TSLP), and gene expression levels of T helper (Th) cells-related cytokines in vivo. The underlying mechanisms of the inhibitory effects of JFEE and JFEE-C on AD were related to attenuating T cell activity through NF-κB/MAPK pathways. In conclusion, this study suggested that JFEE and JFEE-C exhibited anti-atopic efficacy by attenuating T cell activity and might possess a curative potential for T cell-mediated diseases.