The core issue of COVID-19-associated pulmonary aspergillosis (CAPA) may not be simply increased fungal exposure or widespread immune suppression, but rather the failure of intracellular clearance programs after macrophage phagocytosis in the context of severe viral lung injury. Although alveolar macrophages (AMs) can recognize and engulf inhaled Aspergillus spores, the true determinant of antifungal outcomes is their ability to continuously advance the fungal containing compartment into a mature, acidified, and hydrolytically degradable terminal lysosomal environment. This article proposes that the dysfunction of macrophages in CAPA can be understood as an imbalance in the autophagy lysosome clearance axis: Aspergillus fumigatus (A. fumigatus) may actively disrupt phagocytic functionalization and lysosome delivery, while SARS-CoV-2-related lung injury may further weaken autophagy support, organelle quality control, and lysosome terminal execution ability. This framework is intended to integrate available CAPA observations with mechanistic evidence from fungal and viral models, helps to explain the contradictory phenotype of persistent inflammation but inefficient fungal clearance in CAPA, and shifts the research focus from a single autophagy marker or inflammatory indicator to the overall functional integrity of the intracellular clearance program after phagocytosis. Restoring the antifungal clearance ability of macrophages around this axis may provide new mechanistic ideas for host directed interventions of CAPA.
Major depressive disorder is a prevalent psychiatric disease that is closely linked to chronic low-grade neuroinflammation, which is primarily driven by microglia, the primary resident immune cells in the brain. Accumulating studies started to reveal that mitochondria, the powerhouses of the cell, play an important role in microglia-mediated neuroinflammation and neurotoxicity in depression. Stress-induced mitochondrial dysfunction triggers microglial activation through distinct mechanisms including energy metabolism patterns transition, electron transport chain impairment, reactive oxygen species accumulation, mitochondrial DNA damage, imbalanced fission and fusion, autophagy, and mitophagy deficiency, which cause the onset and progression of depression. In this review, we described microglial activation in animal models and clinically depressed patients, summarized current understanding of mitochondrial dysfunction-mediated microglial activation, and emphasized the possible mechanisms by which microglial mitochondrial dysfunction participates in the pathogenesis of depression. Understanding the roles and underlying mechanisms of mitochondrial dysfunction in neuroinflammation and neurotoxicity in depression may shed light on developing novel therapeutic strategies to fight against this devastating mental illness.
Periodontal ligament stem cells (PDLSCs) possess potent immunomodulatory and regenerative properties, positioning them as a promising therapeutic strategy for oral inflammatory diseases. However, the metabolic mechanisms governing PDLSC–immune cell crosstalk, particularly in the context of macrophage-driven inflammation, remain incompletely understood. A Transwell coculture model of PDLSCs and THP-1–derived macrophages was established to investigate PDLSC-mediated regulation of macrophage inflammasome activation and inflammation. Transcriptomic, proteomic, and metabolomic profiling with integrated pathway analysis identified metabolic pathways associated with PDLSC-mediated immunomodulation. Triacetyluridine (TAU) was subsequently investigated as a pyrimidine metabolism-related modulator using network pharmacology, functional enrichment, and molecular docking analyses. Its anti-inflammatory effects were evaluated in macrophages, and tissue-reparative effects were assessed in a murine oral ulcer model. PDLSC coculture markedly suppressed activation of the NLRP3 inflammasome and its downstream mediators, including caspase-1, IL-1β, and IL-18, at both transcriptional and protein levels. In the murine oral ulcer model, PDLSC treatment preserved epithelial architecture, reduced immune cell infiltration, and enhanced expression of regenerative markers. Integrated multiomics analyses identified pyrimidine metabolism as a prominent metabolic pathway altered in macrophages cocultured with PDLSCs, characterized by coordinated changes in pyrimidine metabolites and metabolism-associated proteins. TAU-associated analyses identified pyrimidine metabolism as a principal pathway, with UPP1, TYMP, and DPYD as representative targets, and docking predicted potential interactions of TAU with these enzymes. TAU treatment reproduced several anti-inflammatory and tissue-reparative features associated with PDLSC treatment, suppressing inflammasome-related gene expression in vitro and promoting mucosal healing in vivo. PDLSCs modulate macrophage inflammation in association with coordinated remodeling of Pyrimidine metabolism. Functional studies with TAU further support a role for pyrimidine metabolic regulation in controlling inflammatory responses and tissue repair, highlighting this metabolic pathway as a potential therapeutic target for oral inflammatory diseases.
Remarkable progress has been made in the analysis of dynamic biological information using fluorescent intravital imaging techniques. This minimally invasive technology, which allows for real-time visualization of tissue images within the living body, should bring significant advantages for life science research and human tissue studies. Multiphoton excitation microscopy (MPM), which has been mainly employed for intravital imaging in biological research, is a promising technique for the fluorescence imaging of human tissues. Although fluorescent labeling by genetic modification and the administration of fluorescent reagents is difficult in human tissue imaging, label-free MPM can generate image files composed of nonlinear optical phenomena and autofluorescent signals from living bodies using only near-infrared excitation. Label-free MPM can image human tissues in three dimensions in real time without the need for tissue removal, fixation, or staining. This technique has demonstrated utility in the histopathological examination of several organs and tissues. Additionally, it correlates well with quantitative image analysis, including artificial intelligence- and deep learning-driven methods. These features indicate that label-free MPM has sufficient potential for the advancement of histopathology through high-dimensional analysis. The clinical implementation of label-free MPM will alter histopathological examinations in clinical settings, advancing the discipline of histopathology.
The microbiota-gut-brain (MGB) axis is a dynamic network connecting gut microorganisms and the brain through various signaling pathways, playing a crucial role in the diagnosis and treatment of complex neurological disorders. Bile acids (BAs), synthesized in the liver and transformed by the gut microbiota, are known to modulate gastric inflammation. However, their potential roles within the MGB axis and their impact on neuroinflammation and neurological disorders have not yet been investigated. Deoxycholic acid (DCA) and cholic acid (CA), which are secondary and primary BAs, respectively, were treated to microglial BV-2 cells to find out alteration in the signaling pathway. DCA and CA were administered to healthy mice to examine their effect on neurological function. Clostridium scindens, which converts CA into DCA in the gut, was administered to mice to investigate the potential contribution of gut microbial conversion of CA to DCA to neurological outcomes. Levels of BA-converting bacteria and enzyme were analyzed in human fecal samples. First, we observed that DCA elicited stronger pro-inflammatory response than CA in BV-2 microglial cells and increased NLRP3-associated inflammasome signaling. These responses were attenuated by pharmacological inhibition of FXR and S1PR2, with reduced MAPK/NF-κB and NLRP3-associated signaling. Then, DCA was orally administered to normal mice, and it was found that increased DCA concentration increased glial activation and activated microglial NLRP3-associated signaling in the brain. In addition, DCA administration induced memory impairment and altered the AKT/ERK/CREB/BDNF signaling pathway. The concentration of DCA in the hippocampus of mice was significantly correlated with the fear memory score and neuroinflammatory markers. Co-administration of CA and C. scindens was associated with alterations in memory-related behavioral outcomes. In human-derived samples, we observed that the levels of BA-converting bacteria, including C. scindens, and related enzymes were increased in the feces of patients with mild cognitive impairment. These results demonstrate that DCA promotes NLRP3-associated neuroinflammatory responses and neuronal dysfunction, potentially involving FXR- and S1PR2-related signaling pathways. These findings suggest that elevated DCA exposure may contribute to gut–brain axis dysfunction and cognitive impairment under experimental conditions.
