Aldara Cream Research Articles

Peptide Drones Facilitating the Transdermal Delivery of Antitumor Proteins for Melanoma Treatment

AbstractTopical treatment offers a viable alternative for melanoma patients incompatible with surgical interventions. Herein, the study develops a skin‐penetrating peptide (SPP)‐based peptide drone (PD) for the transdermal delivery of antitumor proteins. To achieve cost‐effective therapeutics, Concanavalin A (ConA), which can be prepared through an extraction method, is loaded onto PDs. Compared with free proteins, ConA‐PD complexes (CPCs) demonstrate significantly greater skin permeation. Moreover, the CPCs exhibit potent anticancer activity both in vitro and in vivo, which substantially surpass the efficacy of the Aldara (imiquimod) cream. The CPC‐treated mouse skin remains clear, whereas Aldara cream induces side effects, including psoriasis‐like skin inflammation. The antimetastatic activity of the PD is identified as another advantage of CPC. The use of ConA as an anticancer agent has been significantly limited due to its high hepatotoxicity; however, the transdermal delivery strategy minimizes its hepatic absorption and, in turn, results in negligible hepatotoxicity. These results demonstrate the potential of the CPC as a novel therapeutic agent or an adjunct to other modalities for melanoma treatment, overcoming the limitations of existing materials while exhibiting superior efficacy.

Deucravacitinib and shikonin combination therapy ameliorates imiquimod-induced psoriasis in mice.

TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. The combination of deucravacitinib and shikonin is a promising clinical application.

Exercise During Pregnancy

It has been established that the synthetic peptide LKEKK affects the ability of IL-12 to regulate the secretory activity of keratinocytes obtained from human psoriatic skin: in the concentration range of 100-1000 nM the peptide increases in a dose-dependent manner the production of IL-10 and IFN-γ as well as suppression of the production of IL- 17 induced by IL-12 in vitro. The peptide with the inverted sequence KKEKL was inactive, which indicates the high specificity of the peptide LKEKK action. An in vivo study of the peptide LKEKK activity in a model of imiquimod (IMQ)-induced psoriasis in mice showed that its daily application to the ear (150 500 µg) together with Aldara cream containing 5% IMQ for 6 days significantly suppresses the development of the inflammatory process.

Synthetic Peptide LKEKK as Potential Antipsoriatic Drag

It has been established that the synthetic peptide LKEKK affects the ability of IL-12 to regulate the secretory activity of keratinocytes obtained from human psoriatic skin: in the concentration range of 100-1000 nM the peptide increases in a dose-dependent manner the production of IL-10 and IFN-γ as well as suppression of the production of IL- 17 induced by IL-12 in vitro. The peptide with the inverted sequence KKEKL was inactive, which indicates the high specificity of the peptide LKEKK action. An in vivo study of the peptide LKEKK activity in a model of imiquimod (IMQ)-induced psoriasis in mice showed that its daily application to the ear (150 500 µg) together with Aldara cream containing 5% IMQ for 6 days significantly suppresses the development of the inflammatory process.

A potential role of mesenchymal stem cells derived from human umbilical cord blood in ameliorating psoriasis-like skin lesion in the rats.

Psoriasis is a common autoimmune inflammatory skin disease, with no clear cause, treated with topical agents and phototherapy, conventional immunosuppressant drugs and biologic agents. Stem cell therapy has generated significant interest in regenerative medicine. The aim of this study was to use mesenchymal stem cell (MSC) therapy compared to the topical application of the standard conventional corticosteroid cream. Forty male adult albino rats were used, divided into four groups, 10 rats each: group I (control), group II (psoriasis-like lesions induced by usage of Aldara cream), group III (treated with betamethasone) and group IV (treated with MSCs). Specimens were stained with haematoxylin and eosin, Masson's trichrome, immune-histochemical technique for CD4, CD8 and CD31. Ultra-sections were prepared for transmission electron microscope (TEM) examination. Mesenchymal stem cells demonstrated efficacy in reduction of disease severity in the form of uniform epidermal thickness covered by a very thin keratin layer. Normally arranged layers of epidermal layers, with a clear border demarcation, were seen between the epidermis and the dermis with apparently intact basement membrane. TEM showed absence of gaps between the tightly connected cells of the basal layer and the resting basement membrane. Application of MSCs raises hope for developing a new, safe and effective therapy for psoriatic patients, avoiding the side effects of betamethasone.

Validation of a chronic imiquimod-induced psoriasiform dermatitis model in Balb/c mice

Abstract We developed a modified imiquimod (IMQ)-induced dermatitis protocol (Horvath et al, Scientific Reports 2019) using Finn chambers to minimize the unwanted systemic side effects of this widely used psoriasis animal model. It enables to perform prolonged imiquimod treatment in a self-control way as well. In the present study we investigate the long-term application of IMQ in this localized model. 20 mg Aldara cream (5% IMQ) or 20 mg vaseline were applied in two Finn chambers on the dorsal skin of Balb/c mice during the first 4 days of the experiment and every second or third day from day 5 to day 15, in separate groups. Vaseline or corticosteroid cream were applied on the intermediate days. Skin thickness, blood perfusion, body weight and skin scaling were measured daily. Histopathological alterations were evaluated on H&E stained sections, inflammatory cytokine concentrations (IL-1β, TNF-α, IL-17, IL-22, IL-23) were measured with Luminex technology. Skin edema increased to 80–120% in the every 2nd or 3rd days treated group. Blood perfusion reached maximal response on day 4 and then gradually decreased until the end of the experiment. Moderate body weight loss was observed on the first 5 days of the experiment. Inflammatory cytokine concentrations in the skin were elevated during the onset of the symptoms (1–5 days) but dropped in the chronic phase (day 10 or 15). Topical corticosteroid treatment significantly reduced skin edema from day 8, but it had no effect on blood perfusion. Our results proved that long-term Aldara application in Finn chambers enables the study of chronic psoriatic skin inflammation. Furthermore, our chronic model may be used to investigate topically applied anti-inflammatory drug candidates in psoriasiform dermatitis.

Comparative Histological Study on the Preventive Role of Acarbose and Calcipotriol/Betamethasone in Mouse Model of Psoriasis-Like Skin Inflammation Induced by Imiquimod

Introduction: Psoriasis is an autoimmune skin disorder that is symptomized by erythema and scaling. Recently, imiquimod (IMQ) has been used to induce skin inflammation in mice to create a psoriasis model.Aim of the Work: To assess the possible preventive potential of acarbose on psoriasis-like skin inflammation induced by IMQ in adult male mice, and to compare it to calcipotriol/betamethasone applied on the same psoriasis mouse model.Materials and Methods: Thirty four BALB/c mice were classified as the following groups: I(Control), II(IMQ): IMQ-model with topically applied Aldara cream, ІII(Acarbose): IMQ-model treated with Glucobay orally, ІV(Calcipotriol/Betamethasone): IMQ-model treated with Calcipoheal-Cort ointment and V(Acarbose+Calcipotriol/Betamethasone): IMQ-model treated with both Glucobay and Calcipoheal-Cort combined. Haematoxylin & Eosin stain and S100 immunohistochemical staining were performed along with electron microscopic study of skin sections. Mean epidermal thickness and mean number of S100 immuno-positive keratinocytes were measured and measurements were statistically analyzed.Results: Group II mice showed psoriasis-like signs of skin inflammation. Groups III and IV mice showed less signs of inflammation which were markedly attenuated by combination of both of the treatments. Group II demonstrated significant acanthosis and abundant infiltrates of inflammatory cells in the dermis and significantly numerous S100 immuno-positive keratinocytes. Groups III and IV showed significant improvement of these changes which were markedly diminished in group V as it showed almost normal histological structure.Conclusion: Acarbose had an overall beneficial effect on psoriasis-mimicking mouse model triggered by IMQ, almost comparable to that demonstrated by calcipotriol/betamethasone. However, combination of both treatments exerted a more powerful therapeutic effect.

Methodological refinement of Aldara-induced psoriasiform dermatitis model in mice

Imiquimod (IMQ)-induced skin inflammation is currently the most widely accepted psoriasis animal model, however, it features several limitations. We have modified the IMQ-model to minimize its systemic effects towards effectively maintaining the characteristic skin reactions. The original protocol (OP) uses 62.5 mg Aldara cream (or vaseline) on the shaved back skin of mice for 4 days. In contrast, in our modified protocol (MP) 25 mg Aldara and vaseline are applied simultaneously in separate Finn chambers over the dorsal skin of mice. In both the OP and MP groups, histology showed unequivocal hallmarks of psoriasiform dermatitis. Additionally, skin scaling and blood perfusion values were similar. While Aldara elicited significantly increased skin thickness in the MP group, significant weight loss, spleen enlargement, increased inflammatory cytokine levels in plasma, and treatment related death were only observed in the OP group. Our new method reproduces psoriatic skin alterations highlighting considerably reduced systemic inflammatory reactions. Possessing psoriasiform and control skin areas on the same mouse also reduces inter-individual differences. Additionally, the new method permits prolonged IMQ treatment studies to mimic the chronic nature of psoriasis. Finally, our experimental approach may also be used in other mouse models, to prevent the undesired systemic effects of topically applied drugs.

The Systemic Response to Topical Aldara Treatment is Mediated Through Direct TLR7 Stimulation as Imiquimod Enters the Circulation

Topical application of Aldara cream, containing the Toll-like receptor 7/8 agonist Imiquimod, is a widely used mouse model for investigating the pathogenesis of psoriasis. We have previously used this model to study the effects of peripheral inflammation on the brain, and reported a brain-specific response characterised by increased transcription, infiltration of immune cells and anhedonic-like behavior. Here, we perform a more robust characterisation of the systemic response to Aldara application and find a potent but transient response in the periphery, followed by a prolonged response in the brain. Mass spectrometry analysis of plasma and brain samples identified significant levels of Imiquimod in both compartments at molar concentrations likely to evoke a biological response. Indeed, the association of Imiquimod with the brain correlated with increased Iba1 and GFAP staining, indicative of microglia and astrocyte reactivity. These results highlight the potency of this model and raise the question of how useful it is for interpreting the systemic response in psoriasis-like skin inflammation. In addition, the potential impact on the brain should be considered with regards to human use and may explain why fatigue, headaches and nervousness have been reported as side effects following prolonged Aldara use.

095 Loss of loricrin exacerbates psoriasis-like skin inflammation through altered dendritic cell homeostasis

Psoriasis is a chronic inflammatory skin disease associated with multiple predisposing factors, and one of susceptible loci known as PSORS4 is on human chromosome 1, in which epidermal differentiation complex (EDC) is located. An EDC gene loricrin (Lor) accounts for a major protein mass of cornified cell envelope (CE), the vital structure for epidermal integrity. In contrast to competent epidermal permeability barrier, Lor knockout (LKO) mice had reduced epidermal mechanical stability of the epidermis resulting from impaired cross-linking of filaggrin and keratin 1/10 in their CEs. Since mechanical stress/trauma can contribute to psoriasis induction and exacerbation, we evaluated the impact of the loss LOR in a psoriasis-like disease model. Reflecting mechanical weakness, application of mechanical stress onto the ear skin resulted in enhanced and sustained keratin 6 (K6) protein expression in LKO epidermis as determined by immunohistochemistry (IHC). LKO mice had significantly increased expression levels of cytokines that initiate psoriatic inflammatory response, including Tnf, Il1b and Ifn1a on quantitative reverse transcription PCR (RT-qPCR). Topical application of imiquimod (Aldara) cream on LKO mice resulted in a severe inflammatory phenotype; ear skin had augmented swelling, and back skin had enhanced erythema and hyperkeratosis accompanied by increased transcriptional expression levels of K6a. Since Ifn-a produced by plasmacytoid dendritic cell (pDC) is known to play a pivotal role in this model, pDC marker expression was analyzed in a steady state. Unchallenged LKO mice had significantly enhanced expression of Bst2 in the ear skin as determined by RT-qPCR and IHC. Taken together, these results indicate that reduced mechanical stability in the epidermis can exacerbate psoriasis-like skin inflammation through the alteration of DC homeostasis.

NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells.

Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.

Tumour necrosis factor-α plays a significant role in the Aldara-induced skin inflammation in mice.

Recently, the Aldara-induced psoriasis-like skin inflammation model in mice has attracted increased attention, due to its dependence on the same immunological pathways and cell types as in human psoriasis. To study the impact of constitutive deficiency of tumour necrosis factor (TNF)-α and its upstream regulator mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK-2, herein MK2) in the Aldara-induced psoriasis-like skin inflammation model. TNF-α knockout (KO), MK2 KO and wild-type (WT) mice divided into separate groups received either 45-mg Aldara cream or control cream for 5 consecutive days. The skin inflammation was evaluated clinically, histologically, and by quantitative reverse transcription-polymerase chain reaction. We found that TNF-α KO mice developed significantly less skin inflammation compared with WT mice, as evaluated clinically and histologically. At the molecular level, we demonstrated that the Aldara-induced mRNA expression of the psoriasis-related inflammatory markers interleukin (IL)-17C, IL-23p19, IL-12p40, IL-17A, IL-22 and S100A8 was significantly decreased in TNF-α KO mice compared with WT mice. No significant difference in the mRNA expression of these inflammatory markers between MK2 KO mice and WT mice was found, although Aldara-treated MK2 KO mice showed a tendency towards a lower mRNA expression of IL-17A and IL-22 compared with WT mice. We were able to demonstrate significantly lower levels of inflammation in TNF-α KO mice compared with WT mice, supporting the use of this model in future studies characterizing the role of TNF-α in psoriasis.

Topical imiquimod yields systemic effects due to unintended oral uptake

Repetitive application of topical imiquimod is used as an experimental model for the induction of psoriasiform skin lesions in mice. The model is characterized by several inflammatory processes, including cytokine production both locally and systemically, cellular infiltration, and splenomegaly. To investigate the production of type I interferons in response to imiquimod-containing Aldara cream, IFNβ-luciferase reporter mice were imaged in vivo and ex vivo. Type I interferons were found to be produced in the skin, but also in the intestinal system caused by unintended ingestion of imiquimod by the mice. Through the use of Elizabethan collars to prevent ingestion, these effects, including psoriasiform lesions were nearly completely prevented. Our findings reveal that topical treatment with Aldara induces a psoriasiform skin inflammation, but that its mode of action depends on ingestion of the chemical, which leads to systemic responses and affects local inflammation. Therefore, potential ingestion of topical treatments during experimental procedures should be taken into account during assessment of cutaneous inflammatory parameters in skin disease models.

Aldara®-induced skin inflammation: studies of patients with psoriasis.

The application of Aldara(®) cream containing 5% imiquimod stimulates Toll-like receptor 7/8 on plasmacytoid dendritic cells, thereby producing a potent immunomodulatory effect. This has been reported to trigger psoriasis. To establish a human model of Aldara-induced psoriasis-like skin inflammation in patients with psoriasis. Nonlesional psoriatic skin of 13 patients was treated with Aldara for 2 or 7days. The skin was evaluated clinically and histologically on days 2, 4 and 7. Cytokine expression in Aldara-treated, lesional and nonlesional psoriatic skin was compared using reverse-transcription quantitative polymerase chain reaction. Nine of the 10 patients receiving application of Aldara under occlusion for 2days developed redness, induration and scaling. Histological analysis revealed focal parakeratosis, acanthosis and perivascular mononuclear infiltration. On days 4 and 7 both clinical and histological signs of inflammation subsided. Two of the three patients treated with Aldara for 7days developed erosions leading to psoriasis on day 21. Cytokine markers of activation of the innate immune system [interferon-α, interferon regulatory factor-7 and interleukin (IL)-1β] were equally expressed in lesional and Aldara-treated skin (n=6). IL-6 and tumour necrosis factor-α were preferentially expressed in Aldara-treated skin. Adaptive immune system activation occurred only partially: IL-23p19 and IL-22 were similarly overexpressed in Aldara-treated and lesional psoriatic skin, but IL-17A and IL-12p40 were significantly underexpressed in Aldara-treated skin compared with lesional psoriatic skin. IL-10 was significantly overexpressed in Aldara-treated skin. We were able to induce psoriasis-like skin inflammation although typical psoriasis did not develop, possibly due to incomplete adaptive immune system recruitment and the powerful stimulation of IL-10 counter-regulation.

Peripheral inflammation affects the central nervous system and biology of the brain

There is a growing pool of evidence to support the hypothesis that events in the periphery, particularly of an inflammatory nature, can have a profound effect on the central nervous system (CNS). Specifically, inflammatory cytokines have been shown to be important mediators of neuropsychiatric disorders and variations in their expression can affect the severity of both depression and disease score, if presenting with specific comorbidities. The mechanisms driving the relationship between the CNS and the periphery remain to be fully understood. To investigate this, we have used a well characterised model of psoriasis-like skin inflammation as a tool to examine the consequential effect of localised peripheral inflammation on the brain. Aldara cream, which contains 5% Imiquimod as the active component, has been shown to induce psoriasis-like skin inflammation when applied repeatedly to the dorsal skin of mice. We have already shown that this model leads to the transcriptional upregulation of a number of classic interferon-stimulated genes (ISGs) in the brain, a response that we do not see mimicked in the peripheral blood leukocytes (PBL) at the same time point. We have since identified the transcriptional upregulation of a number of chemokines in the CNS which may be important for instigating immune cell infiltration. Furthermore, we have found that Aldara treatment causes a reduction in the level of doublecortin staining in the dentate gyrus of the hippocampus, indicating a negative effect on neurogenesis. Finally, a basic behavioural model of anhedonia has allowed us to determine a phenotypic consequence of Aldaratreatment, whereby the burrowing activity of the treated group is significantly reduced compared with the control group.

Melanoma Arising after Imiquimod Use

Imiquimod belongs to the class of 1H-imidazo-[4,5-c]quinolones—drugs originally developed as nucleoside analogues with the aim of finding new potential antiviral agents (Harrison et al., 1988). Indeed, Imiquimod was first released as treatment for genital warts before its actions against skin cancer were studied. Imiquimod is a relatively small sized molecule (Mr = 240.3) and is hydrophobic, allowing it to penetrate the skin epidermal barrier and therefore making it suitable for topical formulations (Gerster et al., 2005). Imiquimod has shown itself effective against skin cancers and precancerous lesions, especially basal cell cancers and actinic keratosis (Salasche et al., 2002, Beutner et al., 1999). There have been reports of Imiquimod being used as topical treatment against cutaneous metastases of melanoma and some authors have reported its use as first-line therapy against melanoma in situ (Smyth et al., 2011, Gagnon, 2011). We report a case of an invasive malignant melanoma arising de novo at the specific site of application of Imiquimod (Aldara cream 5%) for a biopsy-proven superficial BCC. Therefore while Imiquimod has added to our topical armamentarium against skin cancer, care must be exercised in prescribing this treatment and it is especially important to follow up patients regularly.

Aldara-induced psoriasis-like skin inflammation: isolation and characterization of cutaneous dendritic cells and innate lymphocytes.

Psoriasis is a chronic auto-inflammatory skin disease of unknown etiology affecting millions of people worldwide. Dissecting the cellular networks and molecular signals promoting the development of psoriasis critically depends on appropriate animal models. Topical application of Aldara cream containing the Toll-like receptor (TLR)7-ligand Imiquimod induces skin inflammation and pathology in mice closely resembling plaque-type psoriasis in humans. The particular power of the Aldara model lies in examining the early events during psoriatic plaque formation, which is difficult to achieve in patients. Hence, recent reports using this model have challenged currently prevailing concepts concerning the pathophysiology of psoriasis. Here, we describe the induction and phenotype of Aldara-mediated dermatitis in mice and, in particular, analysis of the inflammatory cell infiltrate using flow cytometry.

Langerin neg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice

Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c(+) DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin(+) DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin(neg) DCs in vivo. In conclusion, TLR7-activated Langerin(neg) cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.

IL-12 regulates psoriatic plaque formation by inhibiting γδ T cells (P4033)

Abstract Cytokines are key mediators of immune responses and IL-23 is a critical player in psoriasis pathogenesis. New effective monoclonal antibody directed against common subunit p40 of both IL-12 and IL-23 is currently used in clinics to treat plaque type psoriasis. Recently was shown that Aldara cream, a drug commonly used in the treatment of benign skin disorders, is a potent stimulator of psoriasis-like plaque formation and implicates proinflammatory cytokines like IL-17A, IL-17F and IL-22 in the disease pathogenicity. Using this model we found that mice deficient in p40 as well as mice treated with neutralizing anti-p40 mAbs have a substantially reduced skin inflammation upon Aldara treatment. As anti-p40 Abs target both IL-12 and IL-23, we hypothesed, that IL-12 might have a protective role in psoriatic plaque formation. We found that skin inflammation was highly increased in mice lacking IL-12 (IL-12p35-/-) or when IL-12 signalling (IL-12Rb2-/-) was disrupted. Local injection of IL-12Fc significantly reduced skin inflammation that was corroborated by reduced leucocytes infiltrations as well diminished IL-17A expression in the skin. IL-12 stimulated CD27- γδ T cells secrete lower levels of IL-17A and F compared to their unstimulated controls suggesting direct effect of IL-12 on γδ T cells. Taken together, our findings suggest a protective role of IL-12 in psoriatic inflammation and support the need of introducing more specific treatment targeting the IL-23/IL-17 axis.

Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice

Psoriasis is a common, relapsing inflammatory skin disease characterized by erythematous scaly plaques. Histological manifestations of psoriasis include keratinocyte dysregulation and hyperproliferation, elongated rete ridges, and inflammatory infiltrates consisting of T cells, macrophages, dendritic cells, and neutrophils. Despite the availability of new effective drugs to treat psoriasis, the underlying mechanisms of pathogenesis are still poorly understood. Recent studies have shown that Aldara cream, used to treat benign skin abnormalities, triggers psoriasis-like disease in humans and mice and have implicated Th17 cells in disease initiation. Using this as a model, we found a predominant role for the Th17 signature cytokines IL-17A, IL-17F, and IL-22 in psoriasiform plaque formation in mice. Using gene-targeted mice, we observed that loss of Il17a, Il17f, or Il22 strongly reduced disease the severity of psoriasis. However, we found that Th17 cells were not the primary source of these pathogenic cytokines. Rather, IL-17A, IL-17F, and IL-22 were produced by a skin-invading population of γδ T cells and RORγt(+) innate lymphocytes. Furthermore, our findings establish that RORγt(+) innate lymphocytes and γδ T cells are necessary and sufficient for psoriatic plaque formation in an experimental disease model that closely resembles human psoriatic plaque formation.