RESUMO
Systemic sclerosis (SSc) poses a significant challenge in autoimmunology, characterized by the development of debilitating fibrosis of skin and internal organs. The pivotal role of dysregulated T cells, notably the skewed polarization toward Th2 cells, has been implicated in the vascular damage and progressive fibrosis observed in SSc. In this study, we explored the underlying mechanisms by which cannabinoid receptor 2 (CB2) highly selective agonist HU-308 restores the imbalance of T cells to alleviate SSc. Using a bleomycin-induced SSc (BLM-SSc) mouse model, we demonstrated that HU-308 effectively attenuates skin and lung fibrosis by specifically activating CB2 on CD4+ T cells to inhibit the polarization of Th2 cells in BLM-SSc mice, which was validated by Cnr2-specific-deficient mice. Different from classical signaling downstream of G protein-coupled receptors (GPCRs), HU-308 facilitates the expression of SOCS3 protein and subsequently impedes the IL2/STAT5 signaling pathway during Th2 differentiation. The deficiency of SOCS3 partially mitigated the impact of HU-308. Analysis of a cohort comprising 80 SSc patients and 82 healthy controls revealed an abnormal elevation in the Th2/Th1 ratio in SSc patients. The proportion of Th2 cells showed a significant positive correlation with mRSS score and positivity of anti-Scl-70. Administration of HU-308 to PBMCs and peripheral CD4+ T cells from SSc patients led to the upregulation of SOCS3, which effectively suppressed the aberrantly activated STAT5 signaling pathway and the proportion of CD4+IL4+ T cells. In conclusion, our findings unveil a novel mechanism by which the CB2 agonist HU-308 ameliorates fibrosis in SSc by targeting and reducing Th2 responses. These insights provide a foundation for future therapeutic approaches in SSc by modulating Th2 responses.
Assuntos
Diferenciação Celular , Modelos Animais de Doenças , Receptor CB2 de Canabinoide , Escleroderma Sistêmico , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Células Th2 , Animais , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia , Células Th2/imunologia , Camundongos , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo , Diferenciação Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Humanos , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Feminino , Janus Quinases/metabolismo , Masculino , Camundongos Knockout , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Bleomicina , Agonistas de Receptores de Canabinoides/farmacologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Pessoa de Meia-IdadeAssuntos
Abscesso , Pioderma Gangrenoso , Humanos , Pioderma Gangrenoso/diagnóstico , Masculino , Adulto , Face , Abscesso/diagnóstico , RecidivaRESUMO
Ionogels are promising material candidates for ionotronics due to their excellent ionic conductivity, stretchability, and thermal stability. However, it is challenging to develop 3D printable ionogels with both excellent electrical and mechanical properties. Here, we report a highly conductive and stretchable nanostructured (CSN) ionogel for 3D printing ionotronic sensors. We propose the photopolymerization-induced microphase separation strategy to prepare the CSN ionogels comprising continuous conducting nanochannels intertwined with cross-linked polymeric framework. The resultant CSN ionogels simultaneously achieves high ionic conductivity (over 3 S m-1), high stretchability (over 1500%), low degree of hysteresis (0.4% at 50% strain), wide-temperature-range thermostability (-72 to 250 °C). Moreover, its high compatible with DLP 3D printing enables the fabrication of complex ionogel micro-architectures with high resolution (up to 5 µm), which allows us to manufacture capacitive sensors with superior sensing performances. The proposed CSN ionogel paves an efficient way to manufacture the next-generation capacitive sensors with enhanced performance.
RESUMO
BACKGROUND: The role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161+CD8+ T cell infiltration in PDAC. METHODS: This study included 186 patients with confirmed PDAC histology after radical resection. CD161+CD8+ T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status. RESULTS: We observed significant associations between tumor-infiltrating CD161+CD8+ T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161+CD8+ T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161+CD8+ T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161+CD8+ T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161+CD8+ T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161+CD8+ T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161+CD8+ T cells as a unique subtype of responsive CD8+ T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules. CONCLUSION: CD161+CD8+ T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161+CD8+ T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Linfócitos T CD8-Positivos , Antígeno CA-19-9 , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , PrognósticoRESUMO
Aryl hydrocarbon receptor (AhR) is a key transcription factor that modulates the differentiation of T helper 17 (Th17) cells. How AhR is regulated at the post-translational level in Th17 cells remains largely unclear. Here we identify USP21 as a newly defined deubiquitinase of AhR. We demonstrate that USP21 interacts with and stabilizes AhR by removing the K48-linked polyubiquitin chains from AhR. Interestingly, USP21 inhibits the transcriptional activity of AhR in a deubiquitinating-dependent manner. USP21 deubiquitinates AhR at the K432 residue, and the maintenance of ubiquitination on this site is required for the intact transcriptional activity of AhR. Moreover, the deficiency of USP21 promotes the differentiation of Th17 cells both in vitro and in vivo. Consistently, adoptive transfer of USP21 deficient naïve CD4+ T cells elicits more severe colitis in Rag1-/- recipients. Therefore, our study reveals a novel mechanism in which USP21 deubiquitinates AhR and negatively regulates the differentiation of Th17 cells.