Our current understanding of how sugar metabolism affects inflammatory pathways in macrophages is incomplete. Here, we show that glycogen metabolism is an important event that controls macrophage-mediated inflammatory responses. IFN-γ/LPS treatment stimulates macrophages to synthesize glycogen, which is then channeled through glycogenolysis to generate G6P and further through the pentose phosphate pathway to yield abundant NADPH, ensuring high levels of reduced glutathione for inflammatory macrophage survival. Meanwhile, glycogen metabolism also increases UDPG levels and the receptor P2Y 14 in macrophages. The UDPG/P2Y 14 signaling pathway not only upregulates the expression of STAT1 via activating RARβ but also promotes STAT1 phosphorylation by downregulating phosphatase TC45. Blockade of this glycogen metabolic pathway disrupts acute inflammatory responses in multiple mouse models. Glycogen metabolism also regulates inflammatory responses in patients with sepsis. These findings show that glycogen metabolism in macrophages is an important regulator and indicate strategies that might be used to treat acute inflammatory diseases.

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Malignant pleural effusion (MPE) is a frequent complication of various cancers and often leads to a poor quality of life, prognosis, and life expectancy, and its management remains palliative. New approaches that can effectively treat MPE are highly desirable. Here, we show that methotrexate (MTX)packaging tumor cell-derived microparticles (MTX-MP) act as an effective immunotherapeutic agent to treat patients with MPE by mobilizing and activating neutrophils. We find that MTX-MP perfusion via a pleural catheter elicits the recruitment of neutrophils in patients through macrophage-released CXCL1 and CXCL2. By performing ex vivo experiments, we find that the recruited neutrophils are activated and release reactive oxygen species (ROS) and neutrophil extracellular trap (NET) to kill tumor cells. Neutrophil-released NETs were also able to seal off the damaged endothelium, facilitating MPE resolution in vitro and in tumor-bearing mice. These findings reveal the potential for use of cell-derived materials to package drugs as an immunotherapeutic agent against MPE.

Tumor cell-derived microparticles (T-MP) contain tumor antigen profiles as well as innate signals, endowing them with vaccine potential; however, the precise mechanism by which DCs present T-MP antigens to T cells remains unclear. Here, we show that T-MPs activate a lysosomal pathway that is required for DCs presenting tumor antigens of T-MPs. DCs endocytose T-MPs to lysosomes, where T-MPs increase lysosomal pH from 5.0 to a peak of 8.5 via NOX2-catalyzed reactive oxygen species (ROS) production. This increased pH, coupled with T-MP-driven lysosomal centripetal migration, promotes the formation of MHC class I-tumor antigen peptide complexes. Concurrently, endocytosis of T-MPs results in the upregulation of CD80 and CD86. T-MP-increased ROS activate lysosomal Ca channel Mcoln2, leading to Ca release. Released Ca activates transcription factor EB (TFEB), a lysosomal master regulator that directly binds to CD80 and CD86 promoters, promoting gene expression. These findings elucidate a pathway through which DCs efficiently present tumor antigen from T-MPs to CD8 T cells, potentiating T-MPs as a novel tumor cell-free vaccine with clinical applications. .

Objectives High-salt intake has been demonstrated in link to hypertension, and cardiovascular diseases could be programmed in fetal origins. We determined the influence of high-salt diet during pregnancy on the development of the heart. Methods Fetal cardiac structures, cell cycle, renin–angiotensin system (RAS), and epigenetic alternations in the heart following maternal high salt intake during pregnancy were examined. Results Following exposure to high salt, disorganized myofibrillae and mitochondria cristae loss were found in the fetus, S-phase for cardiac cells was enhanced, plasma angiotensin II decreased, and cardiac angiotensin II increased in the fetus. Angiotensin II-increased S-phase in the fetal cardiac cells was primarily via AT1 receptor mechanisms. AT2 receptor mRNA and protein in the fetal heart were not affected, whereas AT1 receptor protein, AT1a, and AT1b mRNA were increased. DNA methylation was found at the CpG sites that were related to AT1b receptors in the fetal heart. Cardiac AT1 receptor protein in the adult offspring was also higher following exposure to prenatal high salt. Conclusion The results suggest a relationship between high-salt diet in pregnancy and developmental changes of the cardiac cells and renin–angiotensin system.