Frontiers in Immunology最新文献

Skeletal muscle fibrosis is a pathological process characterized by excessive deposition of extracellular matrix (ECM). It commonly occurs in various diseases such as muscular dystrophy, aging, cancer cachexia, and muscle injury. This condition leads to destruction of muscle structure, loss of function, and impaired regeneration, significantly affecting patients' quality of life. This review systematically summarizes the molecular mechanisms underlying skeletal muscle fibrosis. Key signaling pathways include transforming growth factor-beta (TGF-β)/Smad, yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), inflammation and immune regulation, oxidative stress, and microRNA-mediated regulation. The roles of fibro/adipogenic progenitors (FAPs), macrophages, and myofibroblasts in this process are also discussed. Among these, the TGF-β/Smad pathway acts as a central driver of fibrosis by promoting the differentiation of FAPs into myofibroblasts and stimulating ECM synthesis. YAP/TAZ integrates mechanical and biochemical signals, further amplifying the fibrotic response. Inflammation, oxidative stress, and epigenetic regulators such as miRNAs and lncRNAs also contribute through complex networks. Regarding therapeutic strategies, this article highlights various interventions including pharmacological inhibition (e.g., TGF-β inhibitors, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs), antioxidants), gene- and RNA-targeting therapies (e.g., miRNA mimics or inhibitors), cell-based therapies (e.g., Mesenchymal Stem Cells (MSCs)), biological agents (e.g., anti-connective tissue growth factor (CTGF) antibodies), as well as physical and nutritional interventions (e.g., electroacupuncture, magnetic stimulation, natural compounds). These approaches demonstrate strong anti-fibrotic potential by modulating ECM metabolism, the immune microenvironment, and cellular behaviors. However, current research still faces challenges such as disease heterogeneity, optimal treatment timing, drug delivery issues, and long-term safety concerns. Therefore, future studies should focus on developing highly specific targeted therapies, integrating multi-omics technologies and imaging assessments, and advancing personalized combination strategies to ultimately achieve effective prevention and treatment of skeletal muscle fibrosis.

Emerging preclinical evidence challenges the long-standing assumption that Interleukin-1β (IL-1β) uniformly promotes non-small cell lung cancer (NSCLC). We show that, in the context of chemo-immunotherapy, IL-1β enhances anti-tumor immunity by inducing tumor-cell CXCL10 expression and recruiting CD8⁺ T cells, thereby sensitizing "cold" tumors to treatment. These findings contrast sharply with the failure of multiple CANOPY trials targeting IL-1β, suggesting that blockade may be effective only in prevention or early carcinogenesis. Instead, controlled IL-1β activation, guided by biomarkers and combined with chemotherapy plus PD-1 blockade, may represent a promising strategy to overcome resistance in established NSCLC.

Introduction: The transcription of inflammatory genes is rapidly induced by extracellular stimuli through coordinated actions of transcription factors and large coactivator complexes. However, the mechanistic interplay between specific chromatin remodelers and kinase modules in driving the transcriptional burst of early inflammatory genes remains poorly understood. This study investigates the roles of the PBAF chromatin remodeling complex and the Mediator kinase module (MKM) in activating NF-κB-dependent CXCL1, CXCL2, and CXCL3 chemokine genes.

Methods: We employed a combination of molecular and genomic techniques. Protein-protein interactions were analyzed via co-immunoprecipitation (co-IP). Transcriptional outputs of CXCL1-3 genes were measured by quantitative mRNA analysis. Chromatin immunoprecipitation (ChIP) was used to assess the occupancy of RNA polymerase II (Pol II), its elongating form (Pol II-S2P), the MKM subunit CDK8, and the PBAF complex (via its BAF200 subunit) at target gene promoters. Functional contributions of the complexes were dissected using siRNA-mediated knockdown of BAF200 (PBAF) and small-molecule inhibition of the MKM.

Results: PBAF and MKM physically interact with each other and with the NF-κB subunit RELA, and both complexes additively contribute to the transcriptional activation of CXCL1-3 genes. Knockdown of the PBAF-specific subunit BAF200 resulted in the loss of the entire PBAF complex from chromatin, a reduction in total Pol II and CDK8 promoter occupancy, and consequently, impaired gene induction. In contrast, MKM inhibition did not affect PBAF recruitment but specifically reduced the level of elongating Pol II-S2P and transcriptional activation. These data indicate non-redundant, stage-specific functions.

Discussion: Our results demonstrate that the PBAF complex and the Mediator kinase module regulate distinct, sequential steps in the transcription cycle of CXCL1-3 genes. PBAF is critical for the initial promoter recruitment or stabilization of the transcription machinery, while MKM primarily facilitates the transition into productive elongation. Their additive positive effect and physical interaction suggest a coordinated mechanism where PBAF establishes a permissive chromatin context, enabling subsequent MKM-dependent phosphorylation events that drive the transcriptional burst of key inflammatory chemokines.

Introduction: Dysbiosis of the microbiota-gut-brain axis contribute to the neurodegenerative process of Parkinson's disease (PD), and dysbiosis and inflammatory responses represent key mechanisms. This study aims to explore the structural changes in the composition of the gut microbiota and the alterations in the inflammatory response mediated by the TLR4/NF-κB pathway in a rotenone-induced PD mouse model, as well as the correlation between the two.

Methods: The motor coordination and spontaneous locomotor activity of the PD mouse model were evaluated using the Rota-Rod test, pole climbing test and open field test. The expression of α-synuclein (α-syn) and the activation status of the TLR4/NF-κB pathway were analyzed by western blot, quantitative real-time polymerase chain reaction (RT-qPCR) combined with immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was used to quantitatively detect the levels of LPS and pro-inflammatory indicators TNF-α, IL-1β and IL-6. The diversity, composition structure and differential abundance of the gut microbiota were analyzed by 16S rRNA sequencing, and correlation analysis was conducted between some microbiota and inflammatory indicators related to the activation of the TLR4/NF-κB signaling pathway.

Results: Mechanistic investigation revealed that rotenone activated the TLR4/NF-κB signaling pathway in the midbrain substantia nigra (SN) and colon tissues, accompanied by a significant increase in LPS levels and pro-inflammatory indicators. 16S rRNA sequencing analysis revealed that the alpha diversity of the gut microbiota were reduced in the model group, the beta diversity structure was altered. In terms of microbiota composition, at the phylum level, the relative abundance of Bacteroidota decreased, while Actinobacteria and Tenericutes increased. At the family level, the relative abundance of Lachnospiraceae and Bacteroidaceae decreased, while the relative abundance of Erysipelotrichaceae and Akkermansiaceae increased. Correlation analysis indicated that the relative abundance of specific bacterial families was significantly correlated with PD motor function indicators, the expression levels of α-syn mRNA in the midbrain SN, the TLR4/NF-κB pathway, and inflammatory indicators.

Conclusion: This study demonstrates a key role of the TLR4/NF-κB signaling pathway in the microbiota-gut-brain axis of a rotenone-induced PD mouse model, where gut microbiota dysbiosis exhibits a significant correlation with inflammation induced by TLR4/NF-κB activation.

The success of solid organ transplantation (SOT) and the use of immunosuppressants provide patients with terminal conditions hope. Acute immune rejection (AR) in SOT patients, however, has become more noticeable. Our study examined the relationship between AR and patient survival in a variety of organ transplants, including liver, kidney, heart, lung, pancreas, intestine, combined heart-lung, and pancreas-kidney transplantations, using the Scientific Registry of Transplant Recipients (SRTR) database. Our research showed that AR universally reduces survival across all solid organ transplant types. Immunosuppressants exhibit organ-specific efficacy patterns, with divergent impacts on survival and AR risk. For instance, in liver transplants (LT), generic tacrolimus increased AR risk (OR: 1.31; 95% CI: 1.21-1.42), while AZA reduced it (OR: 0.52; 95% CI: 0.44-0.60). In kidney transplants (KT), tacrolimus increased AR risk (OR: 1.24; 95% CI: 1.2-1.28), whereas Cyclosporin reduced it (OR: 0.47; 95% CI: 0.43-0.52). Furthermore, the same immunosuppressant can have varying effects on survival across transplant types; MMF significantly increased the risk of death in LT, HT, LU, KT, HL, and PK patients, but reduced the risk of death in PT patients. Originator and generic immunosuppressants differentially influence survival outcomes and rejection incidence. For example, in heart transplantation (HT), originator cyclosporine improved survival, while generic cyclosporine (EON) was associated with decreased survival and increased AR risk. Overall, our research offers a thorough and methodical evaluation of how various immunosuppressants affect prognosis and how AR affects the survival of patients receiving different kinds of SOT.

Objective: Meningeal lymphatic vessels (mLVs) play a significant role in neurological homeostasis and disease. However, their contribution to brain injury following cerebral venous sinus thrombosis (CVST) remains unknown. This study investigated whether mLV dysfunction influences the pathological progression of CVST by regulating the endoplasmic reticulum (ER) and oxidative stress(OS)pathways.

Method: A total of 65 male C57BL/6J mice were randomly assigned to four groups: sham-operated, CVST; CVST combined with cervical lymph node ligation (CVST + Ligation); and 4-phenylbutyric acid (4-PBA) intervention. The CVST model was established by inducing thrombosis in the superior sagittal sinus. All sample collection and experimental assays were performed at 2 days post-modeling. Neurobehavioral assessment, histopathological staining, immunofluorescence, western blotting, reverse transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and bioinformatics analyses were employed to comprehensively evaluate neurological function, brain injury, inflammatory response, key molecular expression in ER/oxidative stress pathways, and alterations in related signaling pathways following mLV dysfunction.

Result: Compared to the CVST group, mice in the CVST+Ligation group exhibited more severe neurological deficits, aggravated histopathological brain injury, increased neuronal loss, and enhanced cellular apoptosis. Transcriptomic analysis following lymphatic dysfunction revealed significant enrichment of pathways related to inflammatory response, cytokine-cytokine receptor interaction, and endoplasmic reticulum (ER) stress. At the levels of immunofluorescence, ELISA, Western blot, and mRNA expression, lymphatic ligation significantly upregulated markers of ER stress and microglial activation/apoptosis (including GRP78, CHOP, ATF4, p-eIF2α, NLRP3, and IL-1β) (P < 0.05), as well as downstream apoptosis-related proteins (such as PUMA and Caspase-12) (P < 0.05). It also promoted the release of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, and IL-17) (P < 0.05). Administration of the ER stress inhibitor 4-PBA effectively reversed these molecular alterations and significantly alleviated brain injury and neuroinflammation in CVST+Ligation mice.

Conclusion: Dysfunction of mLVs exacerbates brain injury after CVST by promoting neuroinflammation via the ER and oxidative stress pathways. Therapeutically targeting mLVs may represent promising strategies for managing CVST-related neurological injury.

CD25, the α-chain of the interleukin-2 receptor (IL2RA), is a key component of the IL-2 pathway and is essential for the development and stability of regulatory T cells. Loss-of-function variants in IL2RA cause a very rare autosomal recessive disorder marked by early-onset autoimmunity and recurrent infections with an IPEX-like presentation. We report the first two molecularly confirmed cases of IL2RA (CD25) deficiency in Morocco, each carrying a distinct homozygous mutation. Both patients were born to first-cousin parents and presented in early childhood with recurrent respiratory and gastrointestinal infections, severe failure to thrive, chronic diarrhea with celiac-like enteropathy, and autoimmune manifestations including autoimmune hepatitis, dermatitis, and, in one case, autoimmune thyroiditis. Lymphocyte subset counts and immunoglobulin levels were within or above age-appropriate ranges, but flow cytometry showed a complete absence of CD25 expression on CD4⁺ T cells in both children, whereas relatives displayed intermediate levels compatible with carrier status. Targeted next-generation sequencing identified two novel IL2RA variants: a splice-site mutation (c.65-2A>G) and a multi-exon deletion (c.557_795-1625del), both leading to loss of functional CD25. Both variants were absent from population databases and classified as likely pathogenic or pathogenic according to ACMG criteria. These two cases expand the mutational and geographic spectrum of IL2RA deficiency and highlight the importance of considering this diagnosis in infants from consanguineous families who present with unexplained polyautoimmunity and recurrent infections. Simple flow cytometric assessment of CD25 on T cells is a valuable screening tool, and early genetic confirmation is crucial to guide timely hematopoietic stem cell transplantation and genetic counselling.

Introduction: Non-small cell lung cancer (NSLSC) stem cells (CSCs) have been shown to be responsible for bone metastasis by interacting with osteoclasts (OCs) and creating an immunosuppressive environment in the bone pre-metastatic niche. Now, we investigated the interaction among OCs, IL-15-stimulated NK cells and CSCs to understand whether NK cells can interfere with the pro-metastatic crosstalk between OCs and CSCs.

Methods: In vitro co-cultures of autologous OCs, NK cells and spheres enriched for CSC from NSCLC A549 cell line (A549/s) were set up both on plastic and bone slices, and OC activity was evaluated through quantification of tartrate-resistant acid phosphatase and of resorption area. The expression of NK cell receptors and ligands was studied through flow cytometry on NK cells, OCs and CSCs. The NK cell degranulation activity was investigated as CD107a expression.

Results: The number of multinucleated/TRAP⁺ OCs and TRAP activity decreased when OCs were cultured with NK cells, and with NK cells+A549s. In presence of NK cells, A549s adhered to the bone slice surface and grew, suggesting that NK cells promote the growth of cancer cells rather than block it. Next, we studied whether NK cell phenotype and activity could be modulated by OCs and A549s. When NK cells were co-cultured with A549 cells, OCs, or with the combination of OCs and A549s, we observed a significant increase in the cytotoxic subset of CD56⁺CD16⁺ cells, a reduced expression of activating receptors (DNAM-1, NKp44) and an increased expression of inhibitory receptors (TIGIT, TIM3) on NK cells. The NK cell degranulation activity was inhibited by the presence of OCs. The addition of an anti-TIGIT antibody only partially reactivated NK cells, as indicated by a modest control of A549 cell growth, suggesting that NK cell exhaustion was induced by OCs.

Discussion: All together these data show that OCs negatively affect the NK cell cytotoxic activity, allowing the growth of NSCLC CSCs. Our findings reveal a previously unrecognized role of OCs in modulating the immune microenvironment by dampening NK cell function.

Background: Anti-GD2 monoclonal antibody effectively treats high-risk neuroblastoma (HR-NB) by recruiting NK cells for antibody-dependent cellular cytotoxicity (ADCC). We recently developed a cell product containing mature, cytotoxic γδ T and NK cells (GADEKILL), and its potential use as a novel immunotherapy for HR-NB has been investigated.

Methods: The GADEKILL γδ T and NK cells were analyzed by flow cytometry for the expression of activating and inhibitory receptors and for cytotoxicity against NB, both with and without dinutuximab-β, at a 1:1 effector-to-target ratio. NB cell lines with high and low/absent GD2 expression, as well as patient-derived 3D tumor spheres, all GD2-expressing, were used as targets. Comparative analyses were performed between GADEKILL NK and purified NK cells obtained from the same donor leukapheresis. Furthermore, a panel of NB cell lines was tested for the expression of B7H6 (i.e., NKp30 ligand), Human influenza hemagglutinin-tag (HA-TAG) and calreticulin (i.e., NKp46 ligands), and butyrophilin (BTN)2A1 and BTN3A1/2/3 (i.e., TCRVδ2 ligands), and the impact on GADEKILL cytotoxicity was assessed.

Results: Compared to their purified counterparts, GADEKILL NK cells showed: (i) higher expression of NKp30 and NKp44 and lower expression of CD16 and NKG2D, (ii) greater cytotoxicity (CD107a⁺) against GD2^- NB cells, (iii) stronger induction of lysis in low GD2-expressing NB cells and patient-derived 3D tumor spheres, and (iv) comparable ADCC. In addition, both γδ T and NK cells degranulated and consistently induced lysis in a panel of NB cell lines and patient-derived 3D tumor spheres expressing B7H6, calreticulin, HA-TAG, BTN2A1, and BTN3A1/2/3 consistently. Finally, NB cell lysis positively correlated with B7H6 and BTN2A1, and B7H6-blocking experiments revealed a significant decrease in target cell lysis when cells highly expressing B7H6 were used as targets.

Conclusions: Our study demonstrated the potential antineuroblastoma activity of the GADEKILL, supporting its therapeutic use, particularly in the context of relapsed/refractory R/R HR-NB with low GD2 expression.

Introduction: Brucella is a Gram-negative facultative intracellular bacterium that can cause fever, abortion, and other symptoms in humans and various mammals. btpB, a type IV secretion system (T4SS) effector of Brucella, plays a critical role in regulating Brucella infection and inhibiting the host's innate immune response.

Methods: In this study, a btpB mutant strain of Brucella A19 (ΔbtpB) was constructed using homologous recombination, and its biological characteristics, virulence, and immunogenicity were systematically investigated.

Results: The results showed that ΔbtpB exhibited weakened resistance to in vitro stress, while its growth characteristics did not differ significantly from the wild-type strain A19. In the mouse immunization model, ΔbtpB induced weaker splenic pathological damage, and the splenic bacterial load was significantly lower than that of A19, indicating its reduced virulence. Additionally, ΔbtpB infection elicited stronger humoral and cellular immune responses in mice, including higher antibody levels, increased levels of Th1 cytokines (such as IFN-γ and IL-2), and enhanced proliferation and activity of CD8+ cells. Detection of Th1 and Th2 cells revealed that ΔbtpB induced stronger Th1 and Th2 responses in the spleen in the early stage, but the Th2 response weakened in the middle and late stages of infection. Notably, ΔbtpB infection did not suppress natural killer (NK) cell activity and even significantly enhanced its cytotoxic activity compared to the A19 strain.

Conclusion: Our research demonstrates that ΔbtpB leads to a reduced survival capacity of Brucella, while enhancing its immunogenicity. This suggests btpB is an important target for the prevention of Brucella.