Central European Journal of Immunology最新文献

Introduction: The PD-1/PD-L1 immune checkpoint pathway plays a critical role in tumor immune escape and disease progression. This study investigated differences in tumor-infiltrating lymphocytes (TILs) and PD-L1 expression between primary breast cancers and matched metastatic lesions, and their relationships with clinical outcomes.

Material and methods: We retrospectively analyzed 54 female breast cancer patients who underwent radical mastectomy between May 2011 and December 2018 at the Second Affiliated Hospital of Nanchang University and later developed recurrent disease. Immunohistochemical (IHC) analysis was performed on matched primary and metastatic tumor samples to evaluate TILs and PD-L1 expression patterns. Associations between these immune parameters and clinical characteristics were assessed.

Results: IHC analysis of 50 paired primary and metastatic lesions revealed distinct PD-L1+ TIL expression patterns across different molecular subtypes of breast cancer. Patients with PD-L1+ tumors showed significantly shorter median disease-free survival (DFS) and overall survival (OS) compared to those with PD-L1- tumors. We observed significant differences in the immune microenvironment between primary and metastatic sites, with metastatic lesions showing consistently lower TIL density, PD-L1+ TIL density, and tumor PD-L1 expression compared to matched primary tumors.

Conclusions: Our findings demonstrate systematic differences in immune parameters between primary and metastatic breast cancer sites, with reduced immune infiltration in metastatic lesions. The data suggest that targeting the PD-1/PD-L1 pathway may be particularly beneficial in patients with PD-L1+ TIL-high primary tumors, potentially by reinvigorating anti-tumor immune responses.

Introduction: Excessive mucus secretion in airway epithelial cells is a hallmark of various airway inflammatory diseases. Neutrophil elastase (NE) is a recognized inducer of mucus secretion, yet the precise mechanisms underlying this process remain inadequately understood. This study aims to investigate the roles of myristoylated alanine-rich C-kinase substrate (MARCKS), activated CDC42 kinase 1 (ACK1) and cortactin in airway mucin secretion induced by NE.

Material and methods: Human airway epithelial cells were treated with NE following specific siRNA- mediated knockdown of MARCKS, ACK1 and cortactin. Western blotting and immunofluorescence were used to observe the expression and localization of cortactin, MARCKS and ACK1. The interaction between cortactin and ACK1 was analyzed using co-immunoprecipitation, and MUC5AC protein expression was measured using ELISA.

Results: NE stimulation only increased the phosphorylation levels of MARCKS, ACK1, and cortactin in the cells. Silencing MARCKS inhibited the phosphorylation of ACK1, and silencing ACK1 inhibited the phosphorylation of cortactin. Co-immunoprecipitation showed that ACK1 could directly bind to cortactin. The inhibition of MARCKS and cortactin significantly decreased the production of MUC5AC.

Conclusions: NE induces the phosphorylation of MARCKS, which subsequently facilitates the phosphorylation of ACK1. This cascade enhances the phosphorylation of cortactin, ultimately leading to increased mucus secretion. The MARCKS/ACK1/cortactin pathway is a potential therapeutic target for excessive mucus secretion induced by NE.

Introduction: Allergic rhinitis (AR) is a common inflammatory disease of the nasal mucosa mediated by immunoglobulin E (IgE). Astaxanthin (AST) has been demonstrated to attenuate airway inflammation in an asthmatic mouse model. Nonetheless, the precise effect of AST on AR symptoms and the associated mechanism remain unclear.

Material and methods: A mouse AR model was established by ovalbumin (OVA) sensitization and challenge, and AST was administered to AR mice. Human nasal epithelial cells (HNEpCs) were stimulated with recombinant human IL-13 to mimic the AR microenvironment in vitro. Hematoxylin-eosin staining was performed for mouse nasal mucosa histologic analysis. The CCK-8 assay was used to evaluate AST cytotoxicity to HNEpCs. ELISA was employed to determine levels of histamine, OVA-specific IgE, and inflammatory mediators. Oxidative stress-related markers were estimated using corresponding assay kits. Western blotting was implemented to estimate oxidative stress- and HMGB1/TLR4 signaling-related protein levels.

Results: AST administration alleviated nasal symptoms, including sneezing and nasal rubbing, in OVA-triggered AR mice. AST mitigated nasal mucosa pathological damage, reduced histamine, OVA-specific IgE, and inflammatory mediators in the serum, and alleviated oxidative stress in the nasal mucosa of AR mice. AST blocked HMGB1/TLR4/NF-κB signaling transduction in both the nasal mucosa of AR mice and IL-13-treated HNEpCs. AST or TAK-242 (a TLR4 inhibitor) ameliorated inflammatory response and oxidative stress in IL-13-stimulated HNEpCs.

Conclusions: AST treatment ameliorates AR by reducing inflammation and oxidative stress via the HMGB1/TLR4/NF-κB pathway.

Introduction: To explore the mechanism of action of azithromycin on lung oxidative injury and immune function in mice infected with Mycoplasma pneumoniae (MP) based on the nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway.

Material and methods: The lung index, dry/wet weight ratio, inflammatory factor levels in alveolar lavage fluid, serum contents of interferon-γ (IFN-γ) and immunoglobulin G (IgG), oxidative stress markers, peripheral blood levels of T-lymphocyte subsets, pathological changes, and Nrf2, HO-1, and NQO1 expression were assessed.

Results: Compared to the control group, the MP group exhibited elevated lung index, reduced lung dry/wet weight ratio, elevated tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 contents, reduced IL-10 levels, raised IFN-γ, IgG and peripheral blood CD8⁺ levels, reduced CD3⁺ and CD4⁺ levels, CD4⁺/CD8⁺ ratio, and superoxide dismutase (SOD) and glutathione (GSH) activity, elevated malondialdehyde (MDA) contents, destruction of lung tissue structure, elevated pathological scores, and diminished Nrf2, HO-1, and NQO1 levels. Compared with MP and MP + DMSO groups, MP + azithromycin (AZI) and MP + sulforaphane (SFN) groups displayed a reduced lung index, elevated lung dry/wet weight ratio, reduced TNF-α, IL-1β, and IL-6 contents, raised IL-10 content, decreased IFN-γ, IgG, and peripheral blood CD8⁺ levels, increased CD3⁺ and CD4⁺ levels and CD4⁺/CD8⁺ ratio, raised SOD and GSH activity, and diminished MDA content. HE staining demonstrated improved lung tissue structure, diminished pathological scores, and upregulated Nrf2, HO-1, and NQO1 levels after azithromycin and SFN intervention compared to the MP group (all p < 0.05).

Conclusions: Azithromycin ameliorates MP infection-induced lung injury and oxidative stress and strengthens immune function in mice, which may be achieved by activating the Nrf2/ARE signaling pathway.

Introduction: The immunopathogenesis of rheumatoid arthritis (RA) is greatly affected by macrophages. However, the precise mechanisms by which selenium-binding protein 1 (SELENBP1) regulates the interaction between macrophages and synovial fibroblasts remain incompletely understood.

Material and methods: We used macrophages (THP-1) that were activated with lipopolysaccharide (LPS) and interferon γ (IFN-γ), combined with gene knockdown techniques and molecular biology assays, to investigate the role of SELENBP1 in oxidative stress and nuclear factor erythroid 2-related factor 2 (NRF2) signaling activation. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and Transwell assay were used to examine the regulatory effect of macrophage on proliferation and migration of synovial fibroblasts (MH7A).

Results: Bioinformatics analysis revealed significant upregulation of SELENBP1 in RA. LPS/IFN-γ treatment significantly increased SELENBP1 expression in THP-1 cells; promoted reactive oxygen species (ROS) production and oxidative stress, downregulation of NRF2 in the THP-1 cell nucleus, and upregulation of NRF2 in the cytoplasm; and increased proliferation and migration of MH7A cells. Knockdown of SELENBP1 reversed these effects of LPS/IFN-γ on the THP-1 and MH7A cells. In addition, ML385 (NRF2 inhibitor) attenuated the inhibitory effect of SELENBP1 knockdown on the ROS production and oxidative stress of THP-1 cells, as well as proliferation and migration of MH7A cells.

Conclusions: Inflammatory macrophages up-regulated SELENBP1, and knockdown of SELENBP1 inhibited inflammatory macrophage-induced ROS production and oxidative stress levels by activating NRF2 signaling, thereby inhibiting the proliferation and migration of synovial fibroblasts. Highly expressed SELENBP1 promoted the development of RA. These discoveries provide potential molecular targets and mechanistic insights for the development of new therapeutic strategies.

The meta-analysis by Wang et al. aimed to assess the long-term effects of mesenchymal stem cells on complex perianal fistula. The authors concluded that mesenchymal stem cell therapy has a long-term effect on the clinical response of complex perianal fistula and should be widely promoted not only in adults but also in infants and adolescents; however, more research on this topic is needed. We appreciate the authors' hard work, and we also agree with this argument. However, we have several concerns about the study. We think it is necessary to discuss the effect of anti-TNF and immunosuppressive therapy on the effcacy of mesenchymal stem cell treatment for perianal fistula in future trials, in order to optimize treatment strategies in perianal fistula patients and reduce the economic burden of patients. In the future, it will be interesting to assess the safety and feasibility of injection of fibrin glue combined with mesenchymal stem cells in perianal fistula.

Introduction: Acne is a prevalent inflammatory skin condition that occurs in adolescents and can persist into adulthood. CircRNA has been reported to be widely involved in a variety of human diseases. However, the regulatory mechanism of hsa_circ_0001445 in acne has rarely been reported. The purpose is to research the role of hsa_circ_0001445 in acne-induced inflammation and its molecular regulatory mechanism to provide a foundation for the exploration of acne-targeting drugs.

Material and methods: We used the GEO, starBase, and GeneCards databases for bioinformatics analysis. The binding sequences of miR-1298-5p and hsa_circ_0001445 or ESR1 mRNA were predicted by the Circular RNA Interactome or starBase database. Double luciferase reporting assay was applied to verify the regulatory relationship between hsa_circ_0001445, miR-1298-5p, and ESR1. RT-qPCR was used to detect levels of hsa_circ_0001445, miR-1298-5p, and ESR1 mRNA. The secretion levels of interleukin (IL)-6, IL-8, and tumor necrosis factor α (TNF-α) were measured using an ELISA kit.

Results: The luciferase activity was weakened by miR-1298-5p mimics in human keratinocytes and sebocytes transfected with wild-type (wt)-circ1445 and wt-ESR1, respectively. Moreover, the overexpression of hsa_circ_0001445 reduced the miR-1298-5p level and reversed the elevation of IL-6, IL-8, and TNF-α levels in Bio-C. acnes-stimulated keratinocytes and sebocytes. In turn, transfection of miR-1298-5p mimics partially eliminated the inflammatory inhibition of hsa_circ_0001445, which was reversed by co-transfection of pcDNA-ESR1.

Conclusions: Hsa_circ_0001445 improved acne inflammation via sponging miR-1298-5p targeting ESR1.

Cardiotoxicity caused by immune checkpoint inhibitors is one of the most severe and potentially fatal side effects. Hence it is crucial from a therapeutic standpoint to understand the underlying processes and devise countermeasures. This study sought to determine whether the SOCS3/JAK/STAT3 signaling pathway, which controls macrophage polarization, contributes to the cardiotoxicity caused by PD-1/PD-L1 inhibitors. The PD-1/PD-L1 inhibitor BMS-1 (10 mg/kg) was used to create a mouse model of immune checkpoint inhibitor-related cardiotoxicity, and hematoxylin and Masson's trichome tests were used to measure cardiomyocyte apoptosis and cardiotoxicity. The production of M1 factors (tumor necrosis factor α [TNF-α] and interleukin [IL]-1 b), as well as the blood levels of myocardial enzymes (creatine kinase, aspartate transaminase, creatine kinase-MB, and lactate dehydrogenase), were evaluated by ELISA. Echocardiography was used to assess the heart's health. The processes were investigated using flow cytometric analysis, real-time PCR, Western blot, and chromatin immunoprecipitation. We found that the PD-1/PD-L1 inhibitor BMS-1 dramatically reduced tumor weight while considerably impairing cardiac function in melanoma-induced tumor-bearing mice. At the gene and protein levels, it was found that levels of SOCS3, JAK, STAT3, and the inflammatory mediators IL-6 and TNF-α had all significantly decreased. Immune checkpoint inhibitor-induced cardiotoxicity may be linked to major changes in the SOCS3/JAK/STAT3 signaling pathway, as indicated by the knockdown of SOCS3, JAK, and STAT3. Finally, immune checkpoint inhibitor intervention demonstrated a large elevation of CD86+ and MHCII+ as well as a considerable increase in macrophages. These data suggest that the SOCS3/JAK/STAT3 signaling pathway, which controls macrophage polarization, may be linked to cardiotoxicity caused by PD-1/PD-L1 inhibitor therapy.

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease whose treatment is still a challenge. The latest registration of anifrolumab for the treatment of moderate-to-severe SLE raises hopes because of its novel anti-interferon mechanism of action. Anifrolumab, a human monoclonal antibody, selectively binds the interferon α (INF-α) receptor, inhibiting systemic inflammation moderated by interferon pathways. The article presents the first case of an 18-year-old man with severe, relapsing and repeatedly hospitalized SLE, successfully treated with anifrolumab. During a subsequent exacerbation with multi-organ involvement, which could not be controlled despite pulses and high doses of glucocorticoids (GCSs), treatment with anifrolumab was initiated. Clinical improvement was achieved 4 weeks after the first dose. The patient's dose of systemic GCSs was gradually reduced until complete withdrawal. No serious side effects were observed throughout the follow-up period, and the criteria for complete remission were achieved by the patient at month 3 of therapy. After 12 months, therapy was discontinued due to a payer decision. Nevertheless, the patient remains in follow-up 14 months after the completion of therapy on stable treatment with hydroxychloroquine and azathioprine. He is still not taking prednisone. This is the first case in Poland to show the fate of a "real life patient" after completion of anifrolumab therapy, an effective clinical remission of many months without the use of oral GCSs.

Introduction: Polycomb repressive complex 1 (PRC1) is a crucial epigenetic modification complex that plays significant roles in embryonic development, cell differentiation, and tumorigenesis. However, its predictive value and role in immunotherapy remain unclear.

Material and methods: Expression of the PRC1 complex was analyzed through RNA-seq, quantitative PCR, and immunohistochemistry. Then, we utilized the TCGA and GEO databases to cross-validate the prognostic risk. A pan-cancer analysis was conducted, including clinical traits, tumor microenvironment (TME), tumor mutational burden (TMB), stemness indices, and drug sensitivity. Furthermore, we cross-validated the effect of PRC1 on immunotherapy through ROC Plotter and Kaplan-Meier Plotter databases. The immune cell infiltration and signaling pathways were further identified.

Results: The expression of PRC1 differed between tumor and normal tissue in most cases. In particular, the whole group exhibited consistent high abundance in gastric, colorectal, and liver cancer. In addition, the expression of PRC1 can serve as a marker of survival prognosis. The members of PRC1 were also associated with clinical characteristics, immune cell infiltration, immune checkpoint inhibitor (ICI)-related immune indexes, and drug sensitivity. Moreover, high expression of BMI1 can increase resistance to immunotherapy, with a worse prognosis. The expression level of BMI1 can affect the immune-related pathways, as indicated by the gene set enrichment analysis (GSEA).

Conclusions: Our study revealed the expression, prognostic value and mechanism of PRC1 in pan-cancer. Its core member BMI1 can be used as a biomarker for the prognosis of tumor patients and the efficacy of ICIs. It provides a theoretical basis for the implementation of individualized immunotherapy.