glycogen and Lupus-Erythematosus--Systemic

Activated lymphocyte-derived DNA (ALD-DNA) has been reported to drive the polarization of macrophages toward M2b, producing inflammatory cytokines and inducing inflammation, correspondingly playing an essential role in the development of systemic lupus erythematosus (SLE). Recently, accumulating evidence has pinpointed metabolic adaptation as the crucial cell-intrinsic determinant for inflammatory response, in which glucose metabolism is the key event. However, whether and how glucose metabolism was involved in ALD-DNA-induced macrophage inflammatory response and SLE development remains unclear. Herein, we performed glucose metabolomic analyses of ALD-DNA-stimulated macrophages and uncovered increased glycolysis and diminished pentose phosphate pathway (PPP), as well as enhanced glycogenesis. In ALD-DNA-stimulated macrophages, increased glycolysis resulted in higher lactate production, whereas diminished PPP efficiently led to lower levels of nicotinamide adenine dinucleotide phosphate (NADPH) with higher levels of reactive oxygen species (ROS). While blockade of lactate generation exerted no significant effect on macrophage inflammation in response to ALD-DNA, scavenging ROS fundamentally inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Further, cyclic adenosine monophosphate (cAMP), a master for regulating glycogen metabolism, was downregulated by ALD-DNA in macrophages, which subsequently imbalanced glycogen metabolism toward glycogenesis but not glycogenolysis. Administration of cAMP effectively restored glycogenolysis and enhanced PPP, which correspondingly reduced ROS levels and inhibited the inflammatory response of ALD-DNA-stimulated macrophages. Finally, blocking glucose metabolism using 2-deoxy-D-glucose (2-DG) efficiently restricted macrophage inflammatory response and alleviated ALD-DNA-induced lupus disease. Together, our findings demonstrate that ALD-DNA drives the adaptation of glucose metabolism for inducing macrophage inflammatory response in SLE, which might further our understanding of disease pathogenesis and provide clues for interventive explorations.

Topics: Cyclic AMP; DNA; Glucose; Glycogen; Humans; Inflammation; Lactic Acid; Lupus Erythematosus, Systemic; Lymphocytes; Macrophages; Reactive Oxygen Species

Native and functioning platelets in patients with primary myelofibrosis and myeloproliferative syndrome were examined by transmission electron microscopy. Among various types of ultrastructural abnormalities in the platelets, three features were emphasized: hypoplasia of the surface connecting system (SCS) with few orifices, hyperplasia of the dense tubular system, and considerable variety in numbers of granule. Morphological analysis was made on platelets of these patients and of normal subjects. Functional morphology of the abnormal platelets was examined in the aggregate samples either by ADP or collagen and the effluent blood from platelet retention test. The abnormal platelets were more or less indifferent from the aggregates and underwent only to a slight degree the changes observed in normal platelets. They frequently retained their native, round, smooth-surfaced form without pseudpod, and did not show the inward shift of organelles; furthermore, they retained more granules than did normal platelets. From these morphological findings we speculated that these ultrastructurally abnormal platelets had an impaired release reaction as a result of the dysfunction of SCS in passing released substances, of the inability of microfilaments to constrict in expelling these substances and sometimes because of a lack of granules as the sources.

Topics: Adenosine Diphosphate; Blood Platelets; Cell Membrane; Collagen; Cytoplasmic Granules; Glycogen; Golgi Apparatus; Humans; Lupus Erythematosus, Systemic; Microscopy, Electron; Microtubules; Mitochondria; Myeloproliferative Disorders; Platelet Aggregation; Primary Myelofibrosis; Stimulation, Chemical

Topics: Arthritis, Rheumatoid; Cells, Cultured; Cytoplasmic Granules; Fibroblasts; Glycogen; Histocytochemistry; Humans; Inclusion Bodies; Inclusion Bodies, Viral; Lupus Erythematosus, Systemic; Microscopy, Electron; Polysaccharides; Skin; Staining and Labeling

Topics: Arthritis, Rheumatoid; Basophils; Blood Protein Electrophoresis; Glycogen; Humans; Immunoelectrophoresis; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Lupus Erythematosus, Systemic; Lymphocytes; Lymphocytosis; Neutrophils

Topics: Glycogen; Histocytochemistry; Humans; Lupus Erythematosus, Cutaneous; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Radiation Effects; Ultraviolet Rays