Frontiers in Immunology最新文献

Excessive cytokine production is a major complication in severe COVID-19. Treatment with antiviral drugs often elicits a bitter taste through activation of bitter taste receptors (TAS2Rs). Since ectopically expressed TAS2Rs can alter cytokine secretion, we hypothesized that homoeriodictyol (HED), a broad TAS2R ligand, modulates the cytokine response to SARS-CoV-2 peptide pools (PP) in human peripheral blood mononuclear cells (PBMCs). Treatment of PBMCs isolated from healthy donors with PP for 24 h induced the mRNA expression of CXCL9, CCL7, and CCL2, the most of 116 cytokines tested. Protein release of these chemokines was quantified by ELISA after PP treatment for 3, 6, 12, 24, and 48 h. The results identified 24 h as the optimal incubation time to distinguish PP-induced chemokine release among PBMCs, T-cells, and T-cell-depleted PBMCs. PBMCs demonstrated the highest mean fold changes of CXCL9, CCL7, and CCL2 with 12, 52, and 96, respectively. Involvement of TAS2Rs was verified (i) by co-incubation of the PBMCs with PP and HED, which decreased (p<0.01) the PP-induced secretion of CXCL9, CCL7, and CCL2 by a mean of 80%, 96%, and 95%, respectively, and (ii) via an siRNA knock-down approach targeting TAS2R14. TAS2R14 knock-down increased (p<0.05) the CXCL9, CCL7, and CCL2 release after 24 h of PP incubation by 33%, 34%, and 29%, respectively. These results reveal TAS2Rs on human PBMCs being functionally active in the chemokine immune response to SARS-CoV-2-specific peptides, with the broadly tuned TAS2R14 as a promising target for anti-inflammatory immune system regulation in viral infections.

Introduction: Acute lung injury (ALI), frequently triggered by sepsis, is characterized by severe respiratory distress and high mortality, particularly in critically ill or elderly individuals. Xuanqing Hefa formula (XQHF) has been clinically applied to alleviate ALI by reducing pulmonary inflammation; however, its underlying mechanisms remain poorly understood. This study aimed to evaluate the therapeutic effects of XQHF on sepsis-induced ALI using both in vitro and in vivo models, and to explore its potential mechanisms of action.

Materials and methods: Multiple active constituents of XQHF were identified using UPLC-MS/MS. To investigate the therapeutic potential of XQHF against sepsis-induced lung injury, a cecal ligation and puncture (CLP) model was established in mice, while an in vitro pyroptosis model was developed using lipopolysaccharide (LPS) and Nigericin (Nig) stimulation in Immortalized bone marrow-derived macrophages (iBMDMs). The protective effects of XQHF were evaluated through seven-day survival analysis, histopathological examination of lung tissue, pulmonary wet-to-dry weight ratio assessment (W/D), and quantification of total protein in bronchoalveolar lavage fluid (BALF). In addition, inflammatory responses and cellular injury were assessed via ELISA, oxidative stress assays, lactate dehydrogenase (LDH) release, and immunofluorescence staining. The anti-pyroptotic effects of XQHF were further elucidated using western blotting and flow cytometry.

Results: The results demonstrated that XQHF significantly preserved lung tissue architecture by attenuating both inflammatory responses and oxidative stress, thereby improving the survival rate of septic mice. At the molecular level, XQHF inhibited the expression of key pyroptosis-related proteins. Similar protective effects were observed in the LPS + Nigericin-induced pyroptosis model in iBMDMs, where XQHF also reduced apoptosis. Confocal microscopy further confirmed that XQHF markedly decreased the expression of pro-inflammatory cytokines, including IL-1β and IL-18.

Conclusions: Our results suggest that the therapeutic effects of XQHF may be attributed to the synergistic actions of its multiple active constituents, which collectively suppress the inflammatory cascade and attenuate pyroptosis, thereby alleviating lung injury. Furthermore, both in vivo and in vitro experiments demonstrated that XQHF modulates sepsis-induced acute lung injury, at least in part, through the inhibition of the NLRP3/Caspase-1-dependent pyroptosis signaling pathway.

Recovery from a variety of surgical treatments, including arthroscopic rotator cuff repair and anterior cruciate ligament restoration, depends heavily on tendon-bone healing. There is mounting evidence that the polarisation of macrophages, namely M2 polarisation, is a crucial regulating factor in the repair of tendon-bone. Early tendon-bone repair is greatly aided by M1 macrophages, which have a pro-inflammatory nature. Long-term pro-inflammatory activity, however, seriously hinders the healing process. Therefore, one of the most important challenges in tendon-bone healing is to guide macrophages into the anti-inflammatory M2 phenotype. The effect of macrophage polarisation on tendon-bone healing is thoroughly investigated in this paper, along with methods for modifying macrophage polarisation. Importantly, it demonstrates how biomaterials control this process via a variety of signalling channels, providing fresh ideas for creating cutting-edge biomaterials (such as scaffolds, hydrogels, exosomes, etc.) that encourage tendon-bone mending by focusing on immune responses from macrophages.

Introduction: This study aimed to develop a limited sampling strategy (LSS) and predictive equations to accurately estimate the areas under the concentration-time curves (AUC) of extended-release tacrolimus (TAC-ER) and mycophenolic acid (MPA).

Methods: A retrospective analysis of Japanese kidney transplant recipients yielded 90 TAC-ER AUC0-24 (23 patients) and 80 MPA AUC0-12 (29 patients) datasets, which were randomly split into learning and validation datasets. Training datasets were used to generate the LSS model equations based on multiple linear regression analysis, and the coefficient of determination (R2) was used to assess the goodness of fit of regression models. Validation datasets applied the selected training equations to compute error indices, Passing-Bablok's Kendall's τ, and Bland-Altman limits of agreement, thereby assessing predictive bias, accuracy, and precision.

Results and discussion: Four equations (C0-C1-C6, C0-C1-C2-C6, C0-C1-C3-C6, C0-C1-C4-C6) showed strong correlations with the actual AUC (R² > 0.95), with the validation identifying C0-C1-C3-C6 as the most reliable for both TAC-ER and MPA. This study demonstrated that LSS using C0-C1-C3-C6 reliably and accurately estimated both the actual TAC-ER AUC0-24 and MPA AUC0-12 simultaneously in kidney transplant recipients. These equations can be feasibly implemented in outpatient clinical settings to reduce time and cost.

Background: Although the existence of antiphospholipid antibodies (aPL) has been extensively documented as a risk factor for thrombocytopenia, hemolytic anemia, and recurrent miscarriage, their contribution to renal damage in the context of the systemic lupus erythematosus (SLE) is yet to be defined. This meta-analysis investigated the association between aPL and renal injury among patients with SLE.

Methods: A systematic literature search was conducted to determine publications that examined the relationship between the level of aPL and renal functioning in SLE patients in four electronic databases (PubMed, Cochrane Library, Embase, and Web of Science). Funnel plots and Egger's test were utilized to assess the presence of publication bias. Sensitivity analysis and the trim-and-fill method were used in the evaluation of the stability of the results. Subgroup analyses were performed according to study design, geographic region, aPL subtype, publication date, and pathological type of lupus nephritis. Also, the cumulative meta-analyses were conducted by ranking the studies based on the year of publication, sample size, and the Newcastle-Ottawa Scale score.

Results: A total of 34,353 publications were retrieved up to September 12, 2025. After screening, a total of 70 studies (18 case-control, 23 cohort, and 29 cross-sectional) involving 12,456 SLE patients were included. The pooled OR for renal injury in aPL-positive versus aPL-negative patients was 2.09 (1.70-2.58). Subgroup analysis revealed anti-cardiolipin (aCL), lupus anticoagulant (LA), and antiphospholipid syndrome significantly increased the risk of renal injury compared with control groups, 108with OR of 1.71 (1.34-2.18), 2.43 (1.64-3.61), 2.07 (1.48-2.89), respectively. In contrast, no statistically significant increase in renal injury risk was observed in groups positive for anti-β2-glycoprotein I and aPS/PT. Cumulative meta-analyses consistently demonstrated an increased risk of renal injury in aPL-positive patients, and this association remained stable across different publication years, sample sizes, and study quality.

Conclusions: Seropositivity for aPL was significantly associated with an increased risk of renal injury in SLE patients, primarily driven by LA and aCL.

Aims: Acute graft-versus-host disease (aGVHD) after liver transplantation (LT) is a rare but highly lethal complication, with no standardized diagnosis/treatment protocols. Our center successfully treated three patients using a comprehensive antithymocyte globulin (ATG)-based regimen. This study preliminarily evaluates the efficacy of ATG-based regimens for aGVHD, comparing outcomes with a historical cohort that received conventional treatment, to provide initial clinical evidence.

Methods: This retrospective study included three consecutive post allogeneic LT aGVHD patients treated at Tianjin First Central Hospital between January 2024 and August 2025. Their outcomes were compared with those of 10 historical controls who received conventional treatment between January 2019 and December 2023. Given the small sample size, outcomes were primarily compared descriptively and using effect size measures (odds ratio [OR]/median difference), while Fisher's exact and Mann-Whitney U tests were performed for exploratory purposes.

Results: In the ATG treatment group, two patients presented with fever and rash, while one presented with diarrhea; all developed skin involvement, oral ulcers, and myelosuppression, with a median posttransplant onset of 18 days (range: 15-27). Skin biopsy revealed epidermal hyperkeratosis, basal cell vacuolar degeneration, and dermal lymphocytic infiltration. Cases 2 and 3 had donor CD8+ T-cell chimerism. Median onset-to-diagnosis time was 15 days (range: 9-17). Treatment included an ATG-based regimen, tacrolimus tapering/withdrawal, low-dose glucocorticoids, intravenous immunoglobulin (IVIG), janus kinase (JAK) inhibitor (ruxolitinib), and symptomatic supportive care. All three patients achieved complete remission (CR) without serious complications, with a median diagnosis-to-remission time of 35 days (range: 17-50). In this preliminary comparison, the ATG group demonstrated a significantly higher CR rate (100% vs. 20%; p = 0.012, OR = 25.0), a lower infection rate (0% vs. 60%; p = 0.033), and a shorter median remission time (35 days vs. 62 days; p = 0.021, median difference = - 27 days) compared with historical controls.

Conclusion: The diagnosis of aGVHD after LT requires integrating clinical manifestations, rash pathology, and chimerism detection. In this small series, ATG-based therapy was associated with favorable outcomes compared with a historical cohort receiving conventional therapy, suggesting that it may be a promising strategy warranting further evaluation in large-scale clinical studies.

Stroke remains a leading cause of death and disability worldwide, and inflammation is increasingly recognized as a key driver of acute injury and secondary neurodegeneration. Among post-stroke immune mediators, neutrophil extracellular traps (NETs) have emerged as critical amplifiers of thromboinflammation and cerebrovascular injury. Parallel developments highlight microglia and infiltrating macrophages as key regulators of sterile inflammation in ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). However, the bidirectional interaction between NETs and microglia/macrophages has not been comprehensively analyzed despite its translational importance. This review describes the mechanistic pathways by which NET components activate microglial pattern recognition receptors, triggering inflammasome activation, inflammatory signaling cascades, and cytokine release. Activated microglia, in turn, promote neutrophil recruitment and NETosis, creating a self-reinforcing cycle. Evidence from ischemic and hemorrhagic stroke demonstrates how NET-microglia interactions lead to neurovascular complications such as blood-brain barrier disruption, microvascular dysfunction, and neuronal injury. We examine therapeutic strategies targeting NET formation and destruction, microglial modulation, and combination approaches to interrupt this inflammatory axis. We highlight novel biomarker and imaging approaches that may enable personalized immunotherapy. Together, these strategies position the NET-microglia/macrophage axis as a promising immunomodulatory target in ischemic and hemorrhagic stroke, offering new avenues for precision therapy development.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may arise secondary to genetic or acquired triggers. Although HLH has been reported in patients with adenosine deaminase 2 (ADA2) deficiency, to date it has not been reported in individuals harboring pathogenic variants in ERCC6L2, a gene typically linked to inherited bone marrow failure. We report a fatal case of HLH in a 2-year-old girl with persistent fever, cytopenias, hepatosplenomegaly, liver failure, and multiorgan dysfunction. Despite targeted HLH therapy, the disease progressed rapidly. Genetic testing identified a homozygous pathogenic variant in ERCC6L2 and a heterozygous ADA2 variant, which we interpret as indicating a susceptibility background to immune dysregulation, with HLH most plausibly occurring as a secondary, trigger-dependent event. No functional validation was performed, and causal inference cannot be made on this basis. To our knowledge, this is the first documented case of HLH in a patient with a homozygous pathogenic ERCC6L2 variant. The co-occurrence of a heterozygous ADA2 variant may have modulated the hyperinflammatory response. These observations highlight the importance of genetic evaluation and suggest-while not proving-a broader spectrum of genetic contexts associated with pediatric HLH; confirmation will require functional studies and replication.

Background: Interleukin (IL)-38 has been recently identified as an anti-inflammatory cytokine. Polymyositis (PM) and dermatomyositis (DM) are two prevalent clinical inflammatory myopathies. This study aims to investigate the serum concentrations of IL-38 in patients with PM/DM and their association with these conditions.

Methods: Serum IL-38 levels were quantified using the enzyme-linked immunosorbent assay method in a cohort of 117 subjects, comprising 77 patients with myositis (8 with PM and 69 with DM) and 40 healthy controls. A comprehensive assessment of preliminary clinical characteristics was conducted for each participant through physical examination and review of medical records. The diagnostic utility of IL-38 in PM/DM was evaluated using the receiver operating characteristic curve.

Results: The findings revealed that serum IL-38 concentrations were significantly elevated in patients with PM/DM compared to the control group, irrespective of the presence of interstitial lung disease. No significant difference was observed between the PM and DM groups. Furthermore, IL-38 demonstrated a positive correlation with the visual analogue scale, lactate dehydrogenase (LDH), and other inflammatory markers. Finally, IL-38, either independently or in conjunction with LDH, exhibits significant diagnostic potential.

Conclusion: The study's findings reveal that patients with PM/DM who present elevated serum levels of IL-38 also show a positive correlation with LDH levels. This suggests IL-38 may participate in modulating inflammatory immune responses in PM/DM and could serve as a potential candidate indicator for these conditions.