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The Journal of Investigative Dermatology Mar 2022The use of preclinical animal models of psoriasis has significantly increased over the last three decades, with each model having unique strengths and limitations. Some... (Review)
Review
The use of preclinical animal models of psoriasis has significantly increased over the last three decades, with each model having unique strengths and limitations. Some models translate better to human disease, and many have provided unique insight into psoriasis disease pathogenesis. In this comprehensive review, we present a comparative description and discussion of genetic mouse models, xenograft approaches, and elicited methods using cytokine injections into and topical imiquimod onto mice. We provide an inclusive list of genetically modified animals that have had imiquimod applied to or cytokines injected into their skin and describe the outcomes of these manipulations. This review will provide a valuable resource for those interested in working with psoriasis animal models.
Topics: Animals; Cytokines; Disease Models, Animal; Humans; Imiquimod; Mice; Psoriasis; Skin
PubMed: 34953514
DOI: 10.1016/j.jid.2021.06.019 -
Human Vaccines & Immunotherapeutics Jul 2018Genital warts are one of the most common sexually transmitted diseases worldwide. The disease is a result of infection with low-risk types of human papillomaviruses,... (Review)
Review
Genital warts are one of the most common sexually transmitted diseases worldwide. The disease is a result of infection with low-risk types of human papillomaviruses, mostly type 6 and 11. Current therapies for genital warts are mainly ablative, or alternatively topical application of imiquimod cream and sinecatechin (polyphenon E) ointment to the warts. However, low patient compliance and high recurrence rate are significant problems for the treatment of genital warts by imiquimod and ablative therapies. We summarise recent literature in this area and propose combining imiquimod with other therapies to increase the efficacy of imiquimod.
Topics: Administration, Topical; Anus Diseases; Catechin; Condylomata Acuminata; Drug Therapy, Combination; Humans; Imiquimod; Interferon Inducers; Interleukin-10; Papillomaviridae; Recurrence; Treatment Outcome
PubMed: 29505317
DOI: 10.1080/21645515.2018.1445947 -
Protein & Cell Dec 2018Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named...
Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Macrophages are roughly categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation driven by IL-23 with a distinct gene expression profile including defined types of cytokines. The freshly isolated resting mouse peritoneal macrophages were stimulated with different cytokines in vitro, the expression of cytokines and chemokines were detected by microarray, real-time PCR, ELISA and multiple colors flow cytometry. Adoptive transfer of macrophages and imiquimod-induced psoriasis mice were used. In contrast to M1- and M2-polarized macrophages, IL-23-treated macrophages produce large amounts of IL-17A, IL-22 and IFN-γ. Biochemical and molecular studies showed that IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway. T-bet mediates the IFN-γ production in IL-23-treated macrophages. Importantly, IL-23-treated macrophages significantly promote the dermatitis pathogenesis in a psoriasis-like mouse model. IL-23-treated resting macrophages express a distinctive gene expression prolife compared with M1 and M2 macrophages. The identification of IL-23-induced macrophage polarization may help us to understand the contribution of macrophage subpopulation in Th17-cytokines-related pathogenesis.
Topics: Animals; Cell Polarity; Imiquimod; Interleukin-23; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Psoriasis
PubMed: 29508278
DOI: 10.1007/s13238-018-0505-z -
Biological Research Oct 2020Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The...
BACKGROUND
Psoriasis is a common chronic inflammatory skin disease. Keratinocytes hyperproliferation and excessive inflammatory response contribute to psoriasis pathogenesis. The agents able to attenuate keratinocytes hyperproliferation and excessive inflammatory response are considered to be potentially useful for psoriasis treatment. Daphnetin exhibits broad bioactivities including anti-proliferation and anti-inflammatory. This study aims to evaluate the anti-psoriatic potential of daphnetin in vitro and in vivo, and explore underlying mechanisms.
METHODS
HaCaT keratinocytes was stimulated with the mixture of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) to establish psoriatic keratinocyte model in vitro. Cell viability was measured using Cell Counting Kit-8 (CCK-8). Quantitative Real-Time PCR (qRT-PCR) was performed to measure the mRNA levels of hyperproliferative marker gene keratin 6 (KRT6), differentiation marker gene keratin 1 (KRT1) and inflammatory factors IL-1β, IL-6, IL-8, TNF-α, IL-23A and MCP-1. Western blotting was used to detect the protein levels of p65 and p-p65. Indirect immunofluorescence assay (IFA) was carried out to detect p65 nuclear translocation. Imiquimod (IMQ) was used to construct psoriasis-like mouse model. Psoriasis severity (erythema, scaling) was scored based on Psoriasis Area Severity Index (PASI). Hematoxylin and eosin (H&E) staining was performed to examine histological change in skin lesion. The expression of inflammatory factors including IL-6, TNF-α, IL-23A and IL-17A in skin lesion was measured by qRT-PCR.
RESULTS
Daphnetin attenuated M5-induced hyperproliferation in HaCaT keratinocytes. M5 stimulation significantly upregulated mRNA levels of IL-1β, IL-6, IL-8, TNF-α, IL-23A and MCP-1. However, daphnetin treatment partially attenuated the upregulation of those inflammatory cytokines. Daphnetin was found to be able to inhibit p65 phosphorylation and nuclear translocation in HaCaT keratinocytes. In addition, daphnetin significantly ameliorate the severity of skin lesion (erythema, scaling and epidermal thickness, inflammatory cell infiltration) in IMQ-induced psoriasis-like mouse model. Daphnetin treatment attenuated IMQ-induced upregulation of inflammatory cytokines including IL-6, IL-23A and IL-17A in skin lesion of mice.
CONCLUSIONS
Daphnetin was able to attenuate proliferation and inflammatory response induced by M5 in HaCaT keratinocytes through suppression of NF-κB signaling pathway. Daphnetin could ameliorate the severity of skin lesion and improve inflammation status in IMQ-induced psoriasis-like mouse model. Daphnetin could be an attractive candidate for future development as an anti-psoriatic agent.
Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents; Cell Proliferation; Humans; Imiquimod; Inflammation; Keratinocytes; Mice; Mice, Inbred BALB C; Psoriasis; Rabbits; Umbelliferones
PubMed: 33081840
DOI: 10.1186/s40659-020-00316-0 -
Actas Dermo-sifiliograficas Oct 2013Morphea or localized scleroderma is a distinctive inflammatory disease that leads to sclerosis of the skin and subcutaneous tissues. It comprises a number of subtypes... (Review)
Review
Morphea or localized scleroderma is a distinctive inflammatory disease that leads to sclerosis of the skin and subcutaneous tissues. It comprises a number of subtypes differentiated according to their clinical presentation and the structure of the skin and underlying tissues involved in the fibrotic process. However, classification is difficult because the boundaries between the different types of morphea are blurred and different entities frequently overlap. The main subtypes are plaque morphea, linear scleroderma, generalized morphea, and pansclerotic morphea. With certain exceptions, the disorder does not have serious systemic repercussions, but it can cause considerable morbidity. In the case of lesions affecting the head, neurological and ocular complications may occur. There is no really effective and universal treatment so it is important to make a correct assessment of the extent and severity of the disease before deciding on a treatment approach.
Topics: Algorithms; Aminoquinolines; Clinical Trials as Topic; Eosinophilia; Fasciitis; Glucocorticoids; Humans; Imiquimod; Immunosuppressive Agents; Methotrexate; Photochemotherapy; Physical Therapy Modalities; Recurrence; Scleroderma, Localized; Severity of Illness Index
PubMed: 23948159
DOI: 10.1016/j.adengl.2012.10.012 -
EMBO Molecular Medicine Mar 2022Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology-2 domain-containing protein tyrosine...
Psoriasis is a complex chronic inflammatory skin disease with unclear molecular mechanisms. We found that the Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) was highly expressed in both psoriatic patients and imiquimod (IMQ)-induced psoriasis-like mice. Also, the SHP2 allosteric inhibitor SHP099 reduced pro-inflammatory cytokine expression in PBMCs taken from psoriatic patients. Consistently, SHP099 significantly ameliorated IMQ-triggered skin inflammation in mice. Single-cell RNA sequencing of murine skin demonstrated that SHP2 inhibition impaired skin inflammation in myeloid cells, especially macrophages. Furthermore, IMQ-induced psoriasis-like skin inflammation was significantly alleviated in myeloid cells (monocytes, mature macrophages, and granulocytes)-but not dendritic cells conditional SHP2 knockout mice. Mechanistically, SHP2 promoted the trafficking of toll-like receptor 7 (TLR7) from the Golgi to the endosome in macrophages by dephosphorylating TLR7 at Tyr1024, boosting the ubiquitination of TLR7 and NF-κB-mediated skin inflammation. Importantly, Tlr7 point-mutant knock-in mice showed an attenuated psoriasis-like phenotype compared to wild-type littermates following IMQ treatment. Collectively, our findings identify SHP2 as a novel regulator of psoriasis and suggest that SHP2 inhibition may be a promising therapeutic approach for psoriatic patients.
Topics: Animals; Disease Models, Animal; Humans; Imiquimod; Mice; Psoriasis; Skin; Toll-Like Receptor 7
PubMed: 34936223
DOI: 10.15252/emmm.202114455 -
British Journal of Pharmacology Dec 2021Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in...
BACKGROUND AND PURPOSE
Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored.
EXPERIMENTAL APPROACH
We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed.
KEY RESULTS
Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells.
CONCLUSION AND IMPLICATIONS
H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.
Topics: Animals; Cytokines; Disease Models, Animal; Humans; Imiquimod; Inflammation; Keratinocytes; Mice; Mice, Inbred BALB C; NF-kappa B; Psoriasis; Skin
PubMed: 34460100
DOI: 10.1111/bph.15673 -
The Journal of Investigative Dermatology Sep 2022Psoriasis is a recurrent inflammatory skin disorder characterized by epidermal hyperplasia, which is primarily driven by IL-17A. The Hippo-YAP signaling pathway plays a...
Psoriasis is a recurrent inflammatory skin disorder characterized by epidermal hyperplasia, which is primarily driven by IL-17A. The Hippo-YAP signaling pathway plays a vital role in cell survival and tissue growth, and its target gene, AREG, has been reported to promote the development of psoriasis. However, whether IL-17A promotes keratinocyte proliferation through regulating Hippo-YAP signaling has not been explored. In this study, we show that the YAP-AREG pathway is activated in human psoriatic skin and is suppressed by IL-17A antagonist secukinumab and that imiquimod and IL-17A administration activates the YAP-AREG axis in mice epidermis. In vitro studies using HaCaT and normal human epidermal keratinocyte cells suggest that IL-17A enhances AREG expression and keratinocyte proliferation by activating Hippo-YAP signaling. Mechanistically, IL-17A stimulates the recruitment of MST1 to ACT1 in keratinocytes, which leads to reduced MST1-LATS1 interaction and YAP dephosphorylation. Together, our findings reveal a previously unknown mechanism in which IL-17A promotes keratinocyte proliferation in psoriasis, namely through activating YAP-AREG signaling.
Topics: Amphiregulin; Animals; Antibodies, Monoclonal, Humanized; Cell Proliferation; HaCaT Cells; Humans; Imiquimod; Interleukin-17; Keratinocytes; Mice; Psoriasis; Skin
PubMed: 35304250
DOI: 10.1016/j.jid.2022.02.016 -
Sexually Transmitted Diseases Jun 2021No clear guidelines are available for the management of pregnant women with condyloma acuminata, a human papillomavirus-associated benign neoplasm that develops in the...
No clear guidelines are available for the management of pregnant women with condyloma acuminata, a human papillomavirus-associated benign neoplasm that develops in the genital tract. We performed a systematic review to gain a better understanding of the management of condyloma acuminata during pregnancy. In this review, we mainly focused on treatments. We searched PubMed, Google Scholar, and Web of Science to identify studies on the treatment of condyloma acuminata during pregnancy. Thirty articles met the inclusion criteria. The treatment methods described in the literature were laser therapy, cryotherapy, imiquimod, photodynamic therapy, trichloroacetic acid, and local hyperthermia. The most effective treatment remains unclear. Various factors must be considered when deciding how to treat. Based on our assessment of the literature, we recommend cryotherapy as the first-choice treatment and laser therapy as the second-choice treatment. Imiquimod can be considered in cases such as extensive condyloma acuminata that is not easily treated by cryotherapy or laser therapy. In such cases, sufficient informed consent must be obtained from the patient. Cryotherapy, laser therapy, and imiquimod have been administered during all 3 trimesters with no severe adverse effects, but we cautiously recommend reserving laser therapy until the third trimester because of the lower risk of recurrence before delivery. There are still many unclear points regarding the management of condyloma in pregnancy, and further research is needed.
Topics: Condylomata Acuminata; Female; Humans; Imiquimod; Papillomaviridae; Photochemotherapy; Pregnancy; Recurrence
PubMed: 33093288
DOI: 10.1097/OLQ.0000000000001322 -
International Journal of Gynecological... Apr 2023The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of... (Review)
Review
The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) consensus statement on the management of vaginal...
The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.
Topics: Female; Pregnancy; Humans; Colposcopy; Papillomavirus Infections; Quality of Life; Vaginal Neoplasms; Imiquimod; Uterine Cervical Dysplasia; Carcinoma in Situ; Retrospective Studies; Uterine Cervical Neoplasms
PubMed: 36958755
DOI: 10.1136/ijgc-2022-004213