International immunopharmacology最新文献

Introduction: PANoptosis, an inflammatory cell death pathway that integrates pyroptosis, apoptosis, and necroptosis, contributes critically to the pathogenesis of inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). However, the molecular regulation of PANoptosis and its pharmacological intervention remain poorly defined.

Objectives: This study aimed to investigate the regulatory role of XIAP in PANoptosis and to evaluate the therapeutic potential of luteolin, a natural flavonoid, as a pharmacological inhibitor of PANoptosis.

Methods: Murine macrophage models were used to assess PANoptosis induction and inhibition. Structural and biochemical approaches were applied to determine the interaction between luteolin and XIAP. Mitochondrial function, ROS accumulation, oxidized mitochondrial DNA, and z-DNA generation were examined, while autophagy was evaluated as a modulatory mechanism. Therapeutic efficacy was further validated in a poly(I:C)/LPS-induced HLH mouse model.

Results: XIAP was identified as an essential component of the PANoptosome complex, and its knockdown abolished PANoptosis formation. Luteolin directly bound to XIAP, destabilized its structure, and disrupted its interaction with PANoptosome, thereby blocking PANoptosome assembly. Luteolin preserved mitochondrial integrity, reduced ROS accumulation, and inhibited the generation of oxidized mtDNA and z-DNA. Importantly, luteolin enhanced autophagic clearance of damaged mitochondria by relieving XIAP-mediated suppression of autophagy. In vivo, luteolin treatment significantly attenuated systemic inflammation, protected organ function, and improved survival in HLH mice, effects associated with diminished PANoptosome formation and reduced z-DNA accumulation.

Conclusions: This study establishes XIAP as a central regulator of PANoptosis and demonstrates luteolin as a natural inhibitor targeting XIAP to block PANoptosome assembly and mitochondrial dysfunction. These findings provide a novel pharmacological strategy for treating PANoptosis-driven inflammatory diseases.

Post-traumatic joint contracture (PTJC) is driven by persistent joint capsule inflammation and subsequent fibrosis. CC motif chemokine ligand 2 (CCL2) is recognized as a key regulator of sustained inflammation. However, the relevant regulatory mechanism involved in CCL2 production in PTJC has not been fully elucidated. In this study, we investigated whether MIF can facilitate CCL2 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that PTJC-induced elevation of CCL2 levels was synchronous with MIF. Administration of MIF inhibitor 4-IPP at the lesion sites significantly reduced the expression of CCL2. An in vitro study revealed that MIF potently facilitated the production of CCL2 in joint capsule fibroblasts through interaction with CD74 receptor and subsequent activation of JNK/CREB signaling. Interestingly, fibroblast-derived CCL2 promoted macrophage excessive polarization toward M2 phenotype through the CC motif chemokine receptor 2 (CCR2), thereby amplifying chronic inflammation and fibrosis. The inhibition of MIF activity prevented the pro-fibrotic process by decreasing CCL2. Our results provide insights into the new functions of MIF-mediated CCL2 production in fibroblasts, which exacerbates the pathological microenvironment by tuning joint capsule inflammation and fibrosis during PTJC. The present study may provide a new therapeutic strategy for other inflammation- and fibrosis-associated diseases.

Background: Ubiquitin-specific protease 18 (USP18) is a deubiquitinating enzyme initially recognized for its regulatory role in interferon signaling and antiviral immunity. In recent years, aberrant overexpression of USP18 has been increasingly reported across various malignancies, where it is implicated in tumor proliferation and immune evasion. However, its expression profile and mechanistic function in nasopharyngeal carcinoma (NPC) remain largely uncharacterized.

Methods: This study systematically assessed USP18 expression and its clinical relevance in NPC by integrating analyses of public databases with evaluation of clinical tissue specimens. Functional characterization was performed using NPC cell lines engineered for USP18 overexpression or silencing, followed by assays measuring cell proliferation, migration, invasion, apoptosis, and cell cycle dynamics. In vivo validation was conducted via subcutaneous xenograft models in nude mice. Mechanistic insights were further obtained through transcriptomic profiling (RNA-seq) and proteomic analysis of USP18-interacting proteins, leading to the identification of downstream targets and signaling pathways. Rescue experiments were employed to delineate the regulatory network orchestrated by USP18 in NPC.

Results: USP18 was markedly upregulated in NPC tissues and its elevated expression correlated with poor clinical prognosis. Gain- and loss-of-function experiments demonstrated that USP18 significantly enhanced NPC cell proliferation, migration, and invasion, while concurrently suppressing apoptosis. Mechanistically, USP18 was found to interact with the E3 ubiquitin ligase UBR5, thereby attenuating activation of the canonical tumor suppressor pathway p53, resulting in downregulation of its downstream effectors involved in apoptosis and cell cycle arrest. Co-immunoprecipitation assays further validated the physical interaction between USP18 and UBR5, suggesting that USP18 may regulate p53 signaling through UBR5-mediated mechanisms.

Conclusions: This study unveils a previously unrecognized oncogenic mechanism wherein USP18 promotes malignant progression of nasopharyngeal carcinoma via UBR5-dependent suppression of the p53 signaling pathway. These findings highlight USP18 as a promising candidate biomarker and potential therapeutic target in NPC.

The neonatal fc receptor (FcRn) is indispensable in sustaining IgG homeostasis. Recently, the potential role of FcRn in infectious diseases has attracted more attention. However, the function of FcRn in tuberculosis is unclear. The present study aimed to investigate the role of FcRn in regulating BCG infection-induced autophagy in vitro and vivo. FCGRT knockout mice and FcRn knockdown cells were constructed by CRISPR/Cas9 and small interfering RNA. The related indicators of autophagy were detected by transmission electron microscopy, flow cytometry, and western blot. The proteins interacting with FcRn were screened by immunoprecipitation (IP) and mass spectrometry (MS). The results showed more lung injury and less autophagy marker expression in the KO-FcRn mice lungs than wild type (WT) mice after BCG infection (p < 0.01). Meanwhile, si-FcRn restrained BCG-induced macrophage autophagy by activating the PI3K/AKT/m-TOR pathway. Furthermore, FcRn was confirmed to interact with the Y-box binding protein 1 (YBX1) and promote its nuclear translocation. Hence, the current study proved that FcRn protects against BCG-induced lung injury by triggering YBX1-mediated autophagy and suppressing the PI3K /AKT/mTOR signaling pathway. These findings present a novel understanding of the immune role of FcRn in treating and preventing tuberculosis.

Although diarrhea is common in COVID-19, its underlying mechanisms remain unclear. Using clinical data from 3023 patients and single-cell RNA sequencing of colonic tissues, we found that diarrhea was associated with higher disease severity and mortality. scRNA-seq (n = 1 COVID-19 patient with diarrhea) of colonic tissue from deceased patient, and experimental validation to elucidate the mechanisms of SARS-CoV-2-induced diarrhea and identify potential therapeutic targets. Clinical analysis revealed that diarrhea was associated with more severe disease and higher mortality rates. scRNA-seq identified significant downregulation of membrane transporters (SLC9A3, SLC26A3, and SPINT2) in colonic epithelial cells of colonic tissue from one deceased COVID-19 patient. Gene regulon network analysis pinpointed PPARA as a master regulator of these proteins, with its activity suppressed post-infection. Further experiments confirmed that E protein stimulation reduced PPARA activity and the expression of membrane transporters, leading to a diarrheal phenotype (OR = 3.33 for diarrhea as risk factor) in vitro cell culture models. Interestingly, we found PPARA activity was also decreased in SARS-CoV-2-infected lung epithelial cells, where it regulated CFTR expression, contributing to pneumonia. Treatment with PPARA agonists rescued the expression of these proteins, mitigating both diarrheal and pneumonia phenotypes. Our findings reveal a common mechanism by which the SARS-CoV-2 E protein inhibits PPARA activity in both colonic and lung epithelial cells, leading to severe clinical outcomes. PPARA agonists may represent a novel therapeutic strategy for COVID-19-associated diarrhea and pneumonia in vitro cell culture models.

Vildagliptin has been reported to cause liver injury, with clinical findings suggesting the involvement of the immune response. However, the underlying mechanism remains unclear. Vildagliptin possesses a covalent-binding group that may induce an immune response via inflammasome activation. In this study, we examined whether covalent binding of vildagliptin to proteins in differentiated THP-1 or FLC-4 cells leads to inflammasome activation either directly or via damage-associated molecular patterns (DAMPs). We also performed biochemical and histopathological assessments of liver injury in PD-1^-/- mice treated with anti-CTLA-4 antibody and vildagliptin (0.13%). Vildagliptin didn't directly induce IL-1β production and Caspase-1 activity in differentiated THP-1 cells. In contrast, the culture medium of FLC-4 cells incubated with vildagliptin exhibited increased levels. The levels of heat shock protein 40 (HSP40), a DAMP that triggers inflammasome activation, were significantly increased in the culture supernatant. In addition, adducts with a trapping agent were detected in FLC-4 cells, suggesting that covalent binding of vildagliptin induces the release of DAMPs. In mice with impaired immune tolerance due to immune checkpoint blockade, serum AST and ALT levels were significantly elevated 4 weeks after treatment with vildagliptin, and marked granulomatous inflammation was observed in the liver tissues. These results indicate that vildagliptin-induced liver injury occurs via a mechanism whereby the covalent binding of vildagliptin induces the release of HSP40 from hepatocytes, in turn activating inflammasomes. We further demonstrated that the risk of vildagliptin-induced liver injury may be increased by impaired immune tolerance, such as that caused by the co-administration of immune checkpoint inhibitors.

Objective: Sepsis-induced cardiomyopathy (SCM) is a life-threatening complication with poorly understood immune-metabolic drivers. This study aims to uncover the role of autophagy-dependent monocyte reprogramming and its contribution to myocardial injury via CCL7-mediated immune activation in sepsis.

Methods: We performed integrated analysis of bulk and single-cell transcriptomic data from septic patients (GSE65682, GSE152363, GSE167363). Autophagy activity and chemokine signaling were evaluated using bioinformatic approaches including WGCNA, pseudotime trajectory inference, and CellChat communication analysis. Functional validation was conducted through in vitro co-culture systems and in vivo models of LPS-induced sepsis, utilizing CCL7 neutralization, flow cytometry, ELISA, and Western blot.

Results: Single-cell RNA sequencing revealed a distinct C6 monocyte subset characterized by high autophagic flux, elevated CCL7 expression, and an M1-like inflammatory phenotype. Pseudotime analysis positioned C6 monocytes at the terminal end of monocyte differentiation, where they functioned as chemokine hubs amplifying cross-talk with CD8+ T cells, NK cells, and neutrophils. Mechanistically, CCL7 secretion by C6 monocytes promoted autocrine M1 polarization and enhanced CD8+ T cell activation via CCR1/CCR2-dependent PI3K-AKT signaling. In co-culture, CCL7-stimulated CD8+ T cells induced oxidative stress, cytokine release, and cardiomyocyte apoptosis. In vivo, CCL7 neutralization alleviated myocardial injury, reduced cardiac ROS accumulation, and suppressed systemic inflammation.

Conclusions: Our findings identify a pathogenic autophagy-CCL7-monocyte-T cell axis as a central driver of immuno-metabolic dysregulation in SCM. Targeting CCL7-mediated signaling may represent a novel immunomodulatory strategy to restore cardiac immune homeostasis and mitigate sepsis-induced myocardial injury.

Background: The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progression of PD. This study aimed to investigate the specific molecular mechanism underlying the promotion of PD progression by METH through the regulation of microglial polarization and glycolysis.

Methods: METH-induced C57BL/6 mice and BV2 cells were used to construct PD-like neurotoxicity animal and cell models for experimental investigation. Behavioral tests, immunohistochemistry and Nissl staining were used to assess the behavioral ability and neuronal damage of the animals. The levels of related proteins, inflammatory cytokines and glycolysis were detected using immunofluorescence, ELISA, Western blotting, and CCK-8 assays.

Results: METH treatment significantly promoted behavioral disorders in PD mice, reduced the number of TH-positive neurons, and aggravated neuronal damage in the substantia nigra (SN). In addition, METH decreased the M2 marker proteins Arg-1 and CD206 and increased the M1 marker proteins iNOS and CD86; the proinflammatory cytokines TNF-α, IL-β, and IL-6; and glucose uptake, glucose consumption and lactic acid production, thus promoting M1 polarization and glycolytic activity in BV2 cells. In terms of the underlying molecular mechanism, METH treatment significantly increased the level of LPA. METH promotes LPA expression via upregulation of LIPH expression, and activates the PI3K/AKT pathway. Knockdown of LIPH or treatment with BrP-LPA reduces the ability of METH to promote M1 microglial polarization and glycolytic activity. Furthermore, the addition of the PI3K/AKT signaling pathway activator 740 YP weakened the inhibitory effect of BrP-LPA on the above process.

Conclusion: METH may promote M1 polarization and glycolytic activity in microglia by activating LIPH/LPA/PI3K/AKT signaling, thus promoting the progression of PD.

Excessive NLRP3 inflammasome activation is implicated in pathologies like sepsis. While the histone acetyltransferase inhibitor α-methylene-γ-butyrolactone 3 (MB-3) is typically studied in cancer and epigenetic research, its anti-inflammatory potential remains largely unexplored. This study investigated the effect of MB-3 on NLRP3 inflammasome activation in both cellular and animal models. Results demonstrated that MB-3 treatment significantly downregulated NLRP3-associated inflammatory cytokines and proteins in vitro and in vivo. Mechanistic studies revealed that MB-3 acts by dual inhibition of the NLRP3 inflammasome. It disrupted the critical protein interactions between NLRP3-ASC and NLRP3-NEK7 and reduced ASC and NLRP3 oligomerization, thereby blocking the inflammasome assembly. Furthermore, MB-3 exhibited a protective effect on mitochondrial integrity by rescuing the loss of mitochondrial membrane potential and reducing the production of reactive oxygen species (ROS). In conclusion, these findings identify MB-3 as an effective inhibitor of the NLRP3 inflammasome, operating by blocking both the priming and assembly stages of activation. The results suggests that MB-3 is a promising potential therapeutic candidate for the treatment of NLRP3-driven inflammatory diseases.