RESUMEN
Background: Psoriasis is a common chronic inflammatory skin condition. The emergence of psoriasis has been linked to dysbiosis of the microbiota on the skin surface and an imbalance in the immunological microenvironment. In this study, we investigated the therapeutic impact of topical thymopentin (TP5) on imiquimod (IMQ)-induced psoriasis in mice, as well as the modulatory influence of TP5 on the skin immune milieu and the skin surface microbiota. Methods: The IMQ-induced psoriasis-like lesion mouse model was used to identify the targets and molecular mechanisms of TP5. Immunofluorescence was employed to identify differences in T-cell subset expression before and after TP5 therapy. Changes in the expression of NF-κB signaling pathway components were assessed using Western blotting (WB). 16S rRNA sequencing and network pharmacology were used to detect changes in the skin flora before and after TP5 administration. Results: In vivo, TP5 reduced IMQ-induced back inflammation in mice. H&E staining revealed decreased epidermal thickness and inflammatory cell infiltration with TP5. Masson staining revealed decreased epidermal and dermal collagen infiltration after TP5 administration. Immunohistochemistry showed that TP5 treatment dramatically reduced IL-17 expression. Results of the immunoinfiltration analyses showed psoriatic lesions with more T-cell subsets. According to the immunofluorescence results, TP5 dramatically declined the proportions of CD4+, Th17, ROR+, and CD8+ T cells. WB revealed that TP5 reduced NF-κB pathway expression in skin tissues from IMQ-induced psoriasis model mice. 16S rRNA sequencing revealed a significant increase in Burkholderia and Pseudomonadaceae_Pseudomonas and a significant decrease in Staphylococcaceae_Staphylococcus, Aquabacterium, Herbaspirillum, and Balneimonas. Firmicutes dominated the skin microbial diversity after TP5 treatment, while Bacteroidetes, Verrucomicrobia, TM7, Proteobacteria, Actinobacteria, Acidobacteria, Gemmatimonadetes, and other species dominated in the IMQ group. Conclusion: TP5 may treat psoriasis by modulating the epidermal flora, reducing NF-κB pathway expression, and influencing T-cell subsets.
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Imiquimod , Psoriasis , Piel , Timopentina , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/patología , Animales , Ratones , Piel/efectos de los fármacos , Piel/patología , Imiquimod/farmacología , Timopentina/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Femenino , Microbiota/efectos de los fármacos , Masculino , Ratones Endogámicos C57BLRESUMEN
Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy.
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Imiquimod , Células Asesinas Naturales , Activación de Linfocitos , Poli I-C , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Toll-Like , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Poli I-C/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Imiquimod/farmacología , Receptores Toll-Like/metabolismo , Receptores Toll-Like/agonistas , Niño , Oligodesoxirribonucleótidos/farmacología , Citocinas/metabolismo , Femenino , Interferón gamma/metabolismo , Masculino , Imidazoles/farmacología , Citotoxicidad Inmunológica/efectos de los fármacos , Preescolar , Agonistas de los Receptores Toll-LikeRESUMEN
Psoriasis is a common inflammatory systemic disease characterized by pro-inflammatory macrophages activation (M1 macrophage) infiltrated in the dermal layer. How M1 macrophage contributes to psoriasis remains unknown. In this study, we found that adenosine A2A receptor (A2AR) agonist CGS 21680 HCl alleviated the imiquimod (IMQ) and mouse IL-23 Protein (rmIL-23)-induced psoriasis inflammation through reducing infiltration of M1. Conversely, Adora2a deletion in mice exacerbated psoriasis-like phenotype. Mechanistically, A2AR activation inhibited M1 macrophage activation via the NF-κB-KRT16 pathway to reduce the secretion of CXCL10/11 and inhibit Th1/17 differentiation. Notably, the KRT16 expression was first found in M1 macrophage in our study, not only in keratinocytes (KCs). CXCL10/11 are first identified as primarily derived from macrophages and dendritic cells (DCs) rather than KCs in psoriasis using single cell RNA sequencing (scRNA-Seq). In total, the study emphasizes the importance of M1 as an innate immune cell in pathogenesis of psoriasis.
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Inmunidad Adaptativa , Inmunidad Innata , Activación de Macrófagos , Macrófagos , Psoriasis , Receptor de Adenosina A2A , Animales , Humanos , Ratones , Inmunidad Adaptativa/efectos de los fármacos , Adenosina/análogos & derivados , Agonistas del Receptor de Adenosina A2/farmacología , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/inmunología , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Imiquimod/farmacología , Inmunidad Innata/efectos de los fármacos , Queratinocitos/inmunología , Queratinocitos/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Fenetilaminas/farmacología , Psoriasis/inmunología , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2A/genéticaRESUMEN
Local recurrence post-surgery in early-stage triple-negative breast cancer is a major challenge. To control the regrowth of a residual tumor, we have developed an autologous therapeutic hybrid fibrin glue for intra-operative implantation. Using autologous serum proteins as stabilizers, we have optimized high drug-loaded lapatinib-NanoSera (Lap-NS; â¼66% L.C.) and imiquimod-MicroSera (IMQ-MS; â¼92% L.C). Additionally, plasmonic nanosera (PNS) with an â¼67% photothermal conversion efficiency under 980 nm laser irradiation was also developed. While localized monotherapy with either Lap-NS or PNS reduced the tumor regrowth rate, their combination with IMQ-MS amplified the effect of immunogenic cell death with a high level of tumor infiltration by immune cells at the surgical site. The localized combination immunotherapy with a Nano-MicroSera based hybrid fibrin implant showed superior tumor inhibition and survival with significant promise for clinical translation.
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Imiquimod , Femenino , Animales , Humanos , Ratones , Línea Celular Tumoral , Imiquimod/química , Imiquimod/farmacología , Lapatinib/química , Lapatinib/farmacología , Inmunoterapia , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Recurrencia Local de Neoplasia/prevención & control , Fibrina/química , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adhesivo de Tejido de Fibrina/química , Adhesivo de Tejido de Fibrina/farmacología , Ratones Endogámicos BALB C , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
OBJECTIVE: This study aims to utilize PEGylated poly (lactic-co-glycolic acid) (PLGA) nanoparticles as a delivery system for simultaneous administration of the BRAFV600E peptide, a tumor-specific antigen, and imiquimod (IMQ). The objective is to stimulate dendritic cell (DC) maturation, activate macrophages, and facilitate antigen presentation in C57BL6 mice. METHODS: PEG-PLGA-IMQ-BRAFV600E nanoparticles were synthesized using a PLGA-PEG-PLGA tri-block copolymer, BRAFV600E, and IMQ. Characterization included size measurement and drug release profiling. Efficacy was assessed in inhibiting BPD6 melanoma cell growth and activating immature bone marrow DCs, T cells, macrophages, and splenocyte cells through MTT and ELISA assays. In vivo, therapeutic and immunogenic effects potential was evaluated, comparing it to IMQ + BRAFV600E and PLGA-IMQ-BRAFV600E nanoparticles in inhibiting subcutaneous BPD6 tumor growth. RESULTS: The results highlight the successful synthesis of PEG-PLGA-IMQ-BRAFV600E nanoparticles (203 ± 11.1 nm), releasing 73.4% and 63.2% of IMQ and BARFV600E, respectively, within the initial 48 h. In vitro, these nanoparticles demonstrated a 1.3-fold increase in potency against BPD6 cells, achieving ~ 2.8-fold enhanced cytotoxicity compared to PLGA-IMQ-BRAFV600E. Moreover, PEG-PLGA-IMQ-BRAFV600E exhibited a 1.3-fold increase in potency for enhancing IMQ cytotoxic effects and a 1.1- to ~ 2.4-fold increase in activating DCs, T cells, macrophages, and splenocyte cells compared to IMQ-BRAFV600E and PLGA-IMQ-BRAFV600E. In vivo, PEG-PLGA-IMQ-BRAFV600E displayed a 1.3- to 7.5-fold increase in potency for inhibiting subcutaneous BPD6 tumor growth compared to the other formulations. CONCLUSIONS: The findings suggest that PEG-PLGA nanoparticles effectively promote DC maturation, T cell activation, and potentially macrophage activation. The study highlights the promising role of this nanocomposite in vaccine development.
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Células Dendríticas , Imiquimod , Melanoma , Ratones Endogámicos C57BL , Nanopartículas , Polietilenglicoles , Proteínas Proto-Oncogénicas B-raf , Animales , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Polietilenglicoles/química , Proteínas Proto-Oncogénicas B-raf/genética , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Nanopartículas/química , Línea Celular Tumoral , Ratones , Imiquimod/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Femenino , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Liberación de Fármacos , Humanos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/prevención & control , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.
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Mutación con Ganancia de Función , Imiquimod , Factor de Transcripción STAT3 , Células Th17 , Animales , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Células Th17/inmunología , Ratones , Humanos , Imiquimod/farmacología , Piel/patología , Piel/metabolismo , Piel/inmunología , Interleucina-22 , Dermatitis/inmunología , Dermatitis/genética , Dermatitis/patología , Dermatitis/metabolismo , Ratones Endogámicos C57BL , Interleucinas/genética , Interleucinas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Inflamación/genética , Inflamación/metabolismo , Inflamación/inmunología , Inflamación/patologíaRESUMEN
Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.
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Células Dendríticas , Imiquimod , Inflamación , Interleucina-17 , Proteínas de la Membrana , Psoriasis , Transducción de Señal , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Psoriasis/inmunología , Psoriasis/patología , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Interleucina-17/metabolismo , Humanos , Ratones , Inflamación/patología , Inflamación/inmunología , Imiquimod/farmacología , Nucleotidiltransferasas/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Femenino , MasculinoRESUMEN
To overcome the low efficacy of sonodynamic therapy (SDT) caused by hypoxia in the tumor microenvironment, we developed a multiple anti-tumor nanoplatform with synergistic SDT, photothermal therapy (PTT), and ferroptosis effects. PCN-224@FcCaO2/Mn/dihydroartemisinin/imiquimod/PDA (PFC) was prepared by modified with dihydroartemisinin (DHA), imiquimod (R837), CaO2, ferrocene (Fc) and Mn2+ on the PCN-224 (Cu) to achieve self-replenishment of H2O2/O2 and GSH consumption. FcCaO2 decomposed into H2O2 in the tumor microenvironment, triggering the Fenton effect to produce OH, and Cu2+ reduced the potential loss of OH by the depletion of GSH. Under ultrasonic (US) and laser irradiation, PFC exhibits exciting PTT and SDT effects from polydopamine (PDA) and PCN-224. Mn2+ not only promoted the reaction of H2O2 to produce O2 to effectively enhance SDT but also induced tumor cell apoptosis by Mn2+ combined with DHA. PFC induced ferroptosis via Fe interaction with DHA to produce ROS and reduce the expression of GPX4. The released R837 and tumor-associated antigens from SDT/PTT can produce damage associated molecular patterns (DAMPs), which can initiate adaptive immune responses to kill cancer cells, and released again to promote the tumor immune cycle. What's more, SDT/PTT and ferroptosis combined with aPD-L1 can effectively suppress both primary and distant tumor growth.
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Indoles , Estructuras Metalorgánicas , Terapia Fototérmica , Polímeros , Indoles/química , Indoles/farmacología , Polímeros/química , Polímeros/farmacología , Humanos , Animales , Ratones , Terapia Fototérmica/métodos , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Línea Celular Tumoral , Nanopartículas/química , Apoptosis/efectos de los fármacos , Ferroptosis/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Terapia Combinada , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/química , Peróxido de Hidrógeno/farmacología , Imiquimod/farmacología , Metalocenos/química , Metalocenos/farmacologíaRESUMEN
Tumor vaccine, which can effectively prevent tumor recurrence and metastasis, is a promising tool in tumor immunotherapy. However, heterogeneity of tumors and the inability to achieve a cascade effect limit the therapeutic effects of most developing tumor vaccine. We have developed a cascading immunoinducible in-situ mannose-functionalized polydopamine loaded with imiquimod phenylboronic hyaluronic acid nanocomposite gel vaccine (M/P-PDA@IQ PHA) through a boronic ester-based reaction. This reaction utilizes mannose-functionalized polydopamine loaded with imiquimod (M/P-PDA@IQ NAs) as a cross-linking agent to react with phenylboronic-grafted hyaluronic acid. Under near-infrared light irradiation, the M/P-PDA@IQ PHA caused local hyperthermia to trigger immunogenic cell death of tumor cells and tumor-associated antigens (TAAs) releasing. Subsequently, the M/P-PDA@IQ NAs which were gradually released by the pH/ROS/GSH-triggered degradation of M/P-PDA@IQ PHA, could capture and deliver these TAAs to lymph nodes. Finally, the M/P-PDA@IQ NAs facilitated maturation and cross-presentation of dendritic cells, as well as activation of cytotoxic T lymphocytes. Overall, the M/P-PDA@IQ PHA could serve as a novel in situ vaccine to stimulate several key nodes including TAAs release and capture, targeting lymph nodes and enhanced dendritic cells uptake and maturation as well as T cells activation. This cascading immune activation strategy can effectively elicit antitumor immune response.
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Vacunas contra el Cáncer , Ácido Hialurónico , Hidrogeles , Indoles , Nanopartículas , Polímeros , Ácido Hialurónico/química , Polímeros/química , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Indoles/química , Indoles/farmacología , Animales , Ratones , Hidrogeles/química , Nanopartículas/química , Humanos , Imiquimod/química , Imiquimod/farmacología , Células Dendríticas/inmunología , Vacunación , Línea Celular Tumoral , Inmunoterapia/métodos , Reactivos de Enlaces Cruzados/química , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.
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Glioma , Imagen por Resonancia Magnética , Compuestos de Manganeso , Nanomedicina Teranóstica , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Glioma/terapia , Glioma/patología , Animales , Ratones , Humanos , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Vacunas contra el Cáncer/química , Inmunoterapia , Óxidos/química , Óxidos/farmacología , Línea Celular Tumoral , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Barrera Hematoencefálica/metabolismo , Nanogeles/química , Imiquimod/química , Imiquimod/farmacología , NanovacunasRESUMEN
Introduction: Lung cancer's high incidence and dismal prognosis with traditional treatments like surgery and radiotherapy necessitate innovative approaches. Despite advancements in nanotherapy, the limitations of single-treatment modalities and significant side effects persist. To tackle lung cancer effectively, we devised a temperature-sensitive hydrogel-based local injection system with near-infrared triggered drug release. Utilizing 2D MXene nanosheets as carriers loaded with R837 and cisplatin (DDP), encapsulated within a temperature-sensitive hydrogel-forming PEG-MXene@DDP@R837@SHDS (MDR@SHDS), we administered in situ injections of MDR@SHDS into tumor tissues combined with photothermal therapy (PTT). The immune adjuvant R837 enhances dendritic cell (DC) maturation and tumor cell phagocytosis, while PTT induces tumor cell apoptosis and necrosis by converting light energy into heat energy. Methods: Material characterization employed transmission electron microscopy, X-ray photoelectron spectroscopy, phase transition temperature, and near-infrared thermography. In vitro experiments assessed Lewis cell proliferation and apoptosis using CCK-8, Edu, and TUNEL assays. In vivo experiments on C57 mouse Lewis transplant tumors evaluated the photothermal effect via near-infrared thermography and assessed DC maturation and CD4+/CD8+ T cell ratios using flow cytometry. The in vivo anti-tumor efficacy of MDR@SHDS was confirmed by tumor growth curve recording and HE and TUNEL staining of tumor sections. Results: The hydrogel exhibited excellent temperature sensitivity, controlled release properties, and high biocompatibility. In vitro experiments revealed that MDR@SHDS combined with PTT had a greater inhibitory effect on tumor cell proliferation compared to MDR@SHD alone. Combining local immunotherapy, chemotherapy, and PTT yielded superior anti-tumor effects than individual treatments. Conclusion: MDR@SHDS, with its simplicity, biocompatibility, and enhanced anti-tumor effects in combination with PTT, presents a promising therapeutic approach for lung cancer treatment, offering potential clinical utility.
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Cisplatino , Imiquimod , Neoplasias Pulmonares , Ratones Endogámicos C57BL , Animales , Cisplatino/farmacología , Cisplatino/química , Cisplatino/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones , Imiquimod/química , Imiquimod/administración & dosificación , Imiquimod/farmacología , Hidrogeles/química , Apoptosis/efectos de los fármacos , Nanoestructuras/química , Terapia Fototérmica/métodos , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Humanos , Temperatura , Células Dendríticas/efectos de los fármacos , Portadores de Fármacos/química , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Carcinoma Pulmonar de Lewis/patologíaRESUMEN
BACKGROUND: Chemoimmunotherapy has shown promising advantages of eliciting immunogenic cell death and activating anti-tumor immune responses. However, the systemic toxicity of chemotherapy and tumor immunosuppressive microenvironment limit the clinical application. METHODS: Here, an injectable sodium alginate hydrogel (ALG) loaded with nanoparticle albumin-bound-paclitaxel (Nab-PTX) and an immunostimulating agent R837 was developed for local administration. Two murine hepatocellular carcinoma and breast cancer models were established. The tumor-bearing mice received the peritumoral injection of R837/Nab-PTX/ALG once a week for two weeks. The antitumor efficacy, the immune response, and the tumor microenvironment were investigated. RESULTS: This chemoimmunotherapy hydrogel with sustained-release character was proven to have significant effects on killing tumor cells and inhibiting tumor growth. Peritumoral injection of our hydrogel caused little harm to normal organs and triggered a potent antitumor immune response against both hepatocellular carcinoma and breast cancer. In the tumor microenvironment, enhanced immunogenic cell death induced by the combination of Nab-PTX and R837 resulted in 3.30-fold infiltration of effector memory T cells and upregulation of 20 biological processes related to immune responses. CONCLUSIONS: Our strategy provides a novel insight into the combination of chemotherapy and immunotherapy and has the potential for clinical translation.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Ratones , Animales , Hidrogeles/farmacología , Hidrogeles/uso terapéutico , Imiquimod/farmacología , Imiquimod/uso terapéutico , Muerte Celular Inmunogénica , Línea Celular Tumoral , Neoplasias Hepáticas/tratamiento farmacológico , Inmunoterapia/métodos , Inmunidad , Microambiente TumoralRESUMEN
PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.
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Antígeno B7-H1 , Imiquimod , Receptor de Muerte Celular Programada 1 , Prurito , Psoriasis , Animales , Imiquimod/farmacología , Imiquimod/efectos adversos , Prurito/inducido químicamente , Prurito/metabolismo , Psoriasis/inducido químicamente , Psoriasis/complicaciones , Psoriasis/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Antígeno B7-H1/metabolismo , Masculino , Ratones , Transducción de Señal/efectos de los fármacos , Piel/metabolismo , Piel/patología , Ratones Endogámicos C57BL , Enfermedad CrónicaRESUMEN
OBJECTIVE: To elucidate the mechanism of Pentraxin 3 (PTX3) in the pathogenesis of psoriasiform dermatitis using Ptx3-knockout (Ptx3-KO) background mice. METHODS: An Imiquimod (IMQ)-induced murine psoriatic model was created using Ptx3-KO (Ptx3-/-) and wild-type (Ptx3+/+) mice. Skin lesion severity and expression of inflammatory mediators (IL-6 and TNFα) were assessed using PASI score and ELISA, respectively. Cutaneous tissues from the two mice groups were subjected to histological analyses, including HE staining, Masson staining, and Immunohistochemistry (IHC). The PTX3, iNOS, COX2, and Arg1 expressions were quantified and compared between the two groups. We used RNA-seq to clarify the underlying mechanisms of the disease. Flow cytometry was used to analyze systemic Th17 cell differentiation and macrophage polarization. RESULT: The psoriatic region exhibited a higher PTX3 expression than the normal cutaneous area. Moreover, PTX3 was upregulated in HaCaT cells post-TNFα stimulation. Upon IMQ stimulation, Ptx3-/- mice displayed a lower degree of the psoriasiform dermatitis phenotype compared to Ptx3+/+ mice. Consistent with the RNA-seq results, further experiments confirmed that compared to the wild-type group, the PTX3-KO group exhibited a generally lower IL-6, TNFα, iNOS, and COX2 expression and a contrasting trend in macrophage polarization. However, no significant difference in Th17 cell activation was observed between the two groups. CONCLUSIONS: This study revealed that PTX3 was upregulated in psoriatic skin tissues and TNFα-stimulated HaCaT cells. We also discovered that PTX3 deficiency in mice ameliorated the psoriasiform dermatitis phenotype upon IMQ stimulation. Mechanistically, PTX3 exacerbates psoriasiform dermatitis by regulating macrophage polarization rather than Th17 cell differentiation.
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Proteína C-Reactiva , Dermatitis , Psoriasis , Componente Amiloide P Sérico , Animales , Ratones , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dermatitis/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Imiquimod/farmacología , Interleucina-6/metabolismo , Macrófagos/patología , Psoriasis/metabolismo , Psoriasis/patología , Componente Amiloide P Sérico/genética , Componente Amiloide P Sérico/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Humanos , Progresión de la Enfermedad , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Psoriasis is an inflammatory skin disease that occurs repeatedly over time. The natural product of sesquiterpene lactones, Parthenolide (Par), is isolated from Tanacetum parthenium L. (feverfew) which has significant effects on anti-inflammatory. The therapeutic effect of the medication itself is crucial, but different routes of administration of the same drug can also produce different effects. PURPOSE: The aim of our research sought to investigate the ameliorating effects of Par in psoriasis-like skin inflammation and its related mechanism of action. RESULTS: In the IMQ-induced model, intragastric administration of Par reduced the Psoriasis Area and Severity Index (PASI) score, improved skin erythema, scaling, and other symptoms. And Par decreased the expression of Ki67, keratin14, keratin16 and keratin17, and increased the expression of keratin1. Par could reduce IL-36 protein expressions, meanwhile the expression of Il1b, Cxcl1 and Cxcl2 mRNA were also decreased. Par regulated the expression levels of F4/80, MPO and NE. However, skin transdermal administration of Par was more effective. Similarly, Par attenuated IL-36γ, IL-1ß and caspase-1 activated by Poly(I:C) in in vitro and ex vivo. In addition, Par also reduced NE, PR3, and Cathepsin G levels in explant skin tissues. CONCLUSION: Par ameliorated psoriasis-like skin inflammation in both in vivo and in vitro, especially after treatment with transdermal drug delivery, possibly by inhibiting neutrophil extracellular traps and thus by interfering IL-36 signaling pathway. It indicated that Par provides a new research strategy for the treatment of psoriasis-like skin inflammation and is expected to be a promising drug.
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Dermatitis , Trampas Extracelulares , Psoriasis , Sesquiterpenos , Animales , Ratones , Imiquimod/farmacología , Administración Cutánea , Trampas Extracelulares/metabolismo , Piel , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Sesquiterpenos/uso terapéutico , Sesquiterpenos/farmacología , Dermatitis/tratamiento farmacológico , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
Toll-like receptor-7 (TLR7) activation promotes autoimmunity, and metabolic syndrome (MetS) is a common comorbidity in patients with autoimmune disease. We previously demonstrated hyperinsulinemia in TLR7 agonist imiquimod (IMQ)-treated, high-fat diet (HFD)-fed female C57BL/6 mice. Since mouse strains differ in susceptibility to MetS and target organ damage, this study investigated whether 12 weeks of exposure to HFD and IMQ promoted MetS, autoimmunity, and target organ damage in female FVB/N mice. Supporting early-stage autoimmunity, spleen-to-tibia ratio, and anti-nuclear antibodies (ANA) were significantly increased by IMQ. No significant effect of IMQ on urinary albumin excretion or left ventricular hypertrophy was observed. HFD increased liver-to-tibia ratio, which was further exacerbated by IMQ. HFD increased fasting blood glucose levels at the end of 12 weeks, but there was no significant effect of IMQ treatment on fasting blood glucose levels at 6 or 12 weeks of treatment. However, oral glucose tolerance testing at 12 weeks revealed impaired glucose tolerance in HFD-fed mice compared to control diet mice together with IMQ treatment exacerbating the impairment. Accordingly, these data suggest TLR7 activation also exacerbates HFD-induced dysregulation of glucose handling FVB/N mice, supporting the possibility that endogenous TLR7 activation may contribute to dysglycemia in patients with autoimmune disease.
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Enfermedades Autoinmunes , Síndrome Metabólico , Humanos , Femenino , Ratones , Animales , Imiquimod/farmacología , Dieta Alta en Grasa/efectos adversos , Glucemia/metabolismo , Receptor Toll-Like 7/metabolismo , Control Glucémico , Ratones Endogámicos C57BL , Ratones EndogámicosRESUMEN
Cancer immunotherapy is expected to achieve tumor treatment mainly by stimulating the patient's own immune system to kill tumor cells. However, the low immunogenicity of the tumor and the poor efficiency of tumor antigen presentation result in a variety of solid tumors that do not respond to immunotherapy. Herein, we designed a proton-gradient-driven porphyrin-based liposome (PBL) with highly efficient Toll-like receptor 7 (TLR7) agonist (imiquimod, R837) encapsulation (R837@PBL). R837@PBL rapidly released R837 in the acid microenvironment to activate the TLR in the endosome inner membrane to promote bone-marrow-derived dendritic cell maturation and enhance antigen presentation. R837@PBL upon laser irradiation triggered immunogenic cell death of tumor cells and tumor-associated antigen release after subcutaneous injection, activated TLR7, formed in situ tumor nanoadjuvants, and enhanced the antigen presentation efficiency. Photoimmunotherapy promoted the infiltration of cytotoxic T lymphocytes into tumor tissues, inhibited the growth of the treated and abscopal tumors, and exerted highly effective photoimmunotherapeutic effects. Hence, our designed in situ tumor nanoadjuvants are expected to be an effective treatment for treated and abscopal tumors, providing a novel approach for synergistic photoimmunotherapy of tumors.
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Neoplasias , Porfirinas , Humanos , Imiquimod/farmacología , Liposomas/farmacología , Receptor Toll-Like 7/agonistas , Protones , Porfirinas/farmacología , Neoplasias/terapia , Inmunoterapia , Adyuvantes Inmunológicos/farmacología , Antígenos de Neoplasias , Microambiente Tumoral , Línea Celular TumoralRESUMEN
Psoriasis is a chronic, autoimmune skin disease characterized by the deregulated secretion of inflammatory factors in multiple organs. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway mediated by cyclin-dependent kinase 9 (CDK9) is vital for the pathology of psoriasis, leading to the accumulation of inflammatory factors and the progression of skin damage. In this study, we explored the effect of CDK9 inhibition on attenuating the secretion of inflammatory factors and alleviating skin damage in psoriasis models both in vitro and in vivo. Results showed that Atuveciclib, a highly selective CDK9 inhibitor, significantly relieved skin lesions in Imiquimod (IMQ)-induced mice models by lowering the expression of CDK9 and p-RNA Pol II Ser2. Meanwhile, Atuveciclib significantly inhibited STAT3 phosphorylation in mice skin and reduced the levels of key inflammatory cytokines in mice skin, plasma and spleen. In addition to suppressing the secretion of inflammatory cytokines, Atuveciclib ablated the activation of STAT3 induced by tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ). Overall, our findings indicated that the overexpression and hyperfunction of CDK9 promote the progression of psoriasis. Moreover, Atuveciclib interfered with the abnormal STAT3 signaling pathway through the inhibition of CDK9, which ultimately ameliorated psoriatic-like skin inflammation. These suggested that CDK9 inhibition is a potential strategy for batting psoriasis.
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Dermatitis , Psoriasis , Enfermedades de la Piel , Sulfonamidas , Triazinas , Animales , Ratones , Imiquimod/farmacología , Factor de Transcripción STAT3/metabolismo , Quinasa 9 Dependiente de la Ciclina , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Inflamación/inducido químicamente , Transducción de Señal , Citocinas/metabolismoRESUMEN
Nanomedicine in combination with immunotherapy has shown great potential in the cancer treatment, but phototherapeutic nanomaterials that specifically activate the immunopharmacological effects in deep tumors have rarely been developed due to limited laser penetration depth and tumor immune microenvironment. Herein, this work reports a newly synthesized semiconducting polymer (SP) grafted with imiquimod R837 and indoxmid encapsulated micelle (SPRIN-micelle) with strong absorption in the second near infrared window (NIR-II) that can relieve tumor immunosuppression and enhance the photothermal immunotherapy and catabolic modulation on tumors. Immune agonists (Imiquimod R837) and immunometabolic modulators (indoxmid) are covalently attached to NIR-II SP sensors via a glutathione (GSH) responsive self-immolation linker and then loaded into Pluronic F127 (F127) micelles by a temperature-sensitive critical micelle concentration (CMC)-switching method. Using this method, photothermal effect of SPRIN-micelles in deep-seated tumors can be activated, leading to effective tumor ablation and immunogenic cell death (ICD). Meanwhile, imiquimod and indoxmid are tracelessly released in response to the tumor microenvironment, resulting in dendritic cell (DC) maturation by imiquimod R837 and inhibition of both indoleamine 2,3-dioxygenase (IDO) activity and Treg cell expression by indoxmid. Ultimately, cytotoxic T-lymphocyte infiltration and tumor metastasis inhibition in deep solid tumors (9 mm) are achieved. In summary, this work demonstrates a new strategy for the combination of photothermal immunotherapy and metabolic modulation by developing a dual functional polymer system including activable SP and temperature-sensitive F127 for the treatment of deep solid tumors.
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Nanopartículas , Neoplasias , Polietilenos , Polipropilenos , Humanos , Imiquimod/farmacología , Polímeros/farmacología , Micelas , Fototerapia/métodos , Neoplasias/tratamiento farmacológico , Inmunoterapia/métodos , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Janus kinase (JAK) inhibitors are approved for many dermatologic disorders, but their use is limited by systemic toxicities including serious cardiovascular events and malignancy. To overcome these limitations, injectable hydrogels are engineered for the local and sustained delivery of baricitinib, a representative JAK inhibitor. Hydrogels are formed via disulfide crosslinking of thiolated hyaluronic acid macromers. Dynamic thioimidate bonds are introduced between the thiolated hyaluronic acid and nitrile-containing baricitinib for drug tethering, which is confirmed with 1H and 13C nuclear magnetic resonance (NMR). Release of baricitinib is tunable over six weeks in vitro and active in inhibiting JAK signaling in a cell line containing a luciferase reporter reflecting interferon signaling. For in vivo activity, baricitinib hydrogels or controls are injected intradermally into an imiquimod-induced mouse model of psoriasis. Imiquimod increases epidermal thickness in mice, which is unaffected when treated with baricitinib or hydrogel alone. Treatment with baricitinib hydrogels suppresses the increased epidermal thickness in mice treated with imiquimod, suggesting that the sustained and local release of baricitinib is important for a therapeutic outcome. This study is the first to utilize a thioimidate chemistry to deliver JAK inhibitors to the skin through injectable hydrogels, which has translational potential for treating inflammatory disorders.