International immunopharmacology最新文献

Breslow thickness (BT), a parameter measuring the depth of invasion of abnormally proliferating melanocytes, is a key indicator of melanoma severity and prognosis. However, the mechanisms underlying the increase in BT remain elusive. Utilizing data from The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma (SKCM), we identified a set of BT-related molecules and analyzed their expression and genomic heterogeneity across pan-cancerous and normal tissues. Through consensus clustering, we identified two distinct BT phenotypes in melanoma, which exhibited significant differences in clinical, genomic, and immune infiltration characteristics. High BT molecular expression was associated with reduced CD8+ T cell infiltration and poor immunotherapy response, potentially mediated by the Macrophage Migration Inhibitory Factor (MIF) signaling pathway. In vitro experiments confirmed that BT molecules, including TRIM29, SERPINB5, and RAB25, promoted melanoma development through distinct mechanisms. Notably, fibroblast-derived TRIM29 and B-cell-derived RAB25 interacted with SPP1+ monocytes/macrophages via different pathways. Our findings suggest that genomic variations leading to imbalanced expression of BT molecules across cancers contribute to increased BT, which is closely linked to an immunosuppressive microenvironment. The involvement of multiple cell types and complex intercellular interactions underscores the importance of evaluating dynamic cellular crosstalk in the tumor microenvironment to better understand BT increases and develop more effective immunotherapeutic strategies.

During the process of acute lung injury (ALI) associated with sepsis, the α7nAChR in the cholinergic anti-inflammatory pathway (CAP) plays a crucial role. However, the roles of electroacupuncture (EA) and specialized pro-resolving mediators (SPMs) in this context remain unclear. In this study, we demonstrated that EA activates CAP via α7nAChR, reducing lung permeability and inflammatory cytokine release. Our results highlighted lipoxin A4 (LXA4) as a crucial SPM in this process. EA was shown to enhance LXA4 synthesis and alleviate symptoms in patients with sepsis-related acute respiratory distress syndrome (ARDS). Studies using α7nAChR-deficient mice confirmed its essential role in LXA4 regulation. Macrophages in bronchoalveolar lavage fluid (BALF) were identified as key contributors to the protective effects of LXA4, further supported by experiments involving pulmonary macrophage depletion. In summary, we discovered a novel anti-inflammatory pathway where EA activates α7nAChR, leading to increased LXA4 production and lung protection.

Background: Mitochondrial dysfunction induces chondrocyte senescence, thereby precipitating articular cartilage (AC) degeneration in the pathogenesis of osteoarthritis (OA). Although the transfer of mitochondria from mesenchymal stem cells (MSCs) to host cells and their potential protective role have been demonstrated, whether MSCs can alleviate chondrocyte mitochondrial dysfunction or reverse OA progression remains unclear.

Methods: A mitochondrial tracer was used to investigate the transfer of mitochondria-rich extracellular vesicles (MEV) derived from the culture supernatant of human synovial fluid-derived mesenchymal stem cells (hSF-MSCs). Human articular chondrocytes (hACs) impaired by oxidative stress co-incubated with MEV were used for experimental research in vitro. Healthy hACs and stressed hACs were cultured separately acting as the control groups. The MEV was injected into the OA rats' knee joint serving as experimental group. Healthy and OA rats were served as the control groups. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot (WB), enzyme- linked immunosorbent assay (ELISA), flow cytometry (FC), immunofluorescence (IF), fluorescence spectrophotometer (FS), immunohistochemistry (IHC) and other methods are used to analyze the effect of MEV on hACs and OA progression.

Results: MEV derived from hSF-MSCs could transfer into hACs. Compared to the negative control group, co-incubation with MEV resulted in a significant down-regulation of oxidative stress markers and senescence-associated proteins in hACs, while improved mitochondrial function of hACs. Moreover, the MEV could traverse the dense interstitial layer and migrate towards the deeper cartilage, while intra-articular injection of MEV could effectively attenuate AC degeneration.

Conclusion: The transfer of MEV derived from hSF-MSCs represents a promising strategy for safeguarding AC, thereby offering a potential avenue and mechanism for the treatment of OA.