1. Macrophage inflammatory state in Type 1 diabetes: triggered by NLRP3/iNOS pathway and attenuated by docosahexaenoic acid.
- Author
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Davanso MR, Crisma AR, Braga TT, Masi LN, do Amaral CL, Leal VNC, de Lima DS, Patente TA, Barbuto JA, Corrêa-Giannella ML, Lauterbach M, Kolbe CC, Latz E, Camara NOS, Pontillo A, and Curi R
- Subjects
- Adult, Animals, Cells, Cultured, Cytokines metabolism, Diabetes Mellitus, Experimental chemically induced, Diabetes Mellitus, Experimental enzymology, Diabetes Mellitus, Experimental immunology, Diabetes Mellitus, Type 1 chemically induced, Diabetes Mellitus, Type 1 enzymology, Diabetes Mellitus, Type 1 immunology, Female, Humans, Inflammation chemically induced, Inflammation enzymology, Inflammation immunology, Inflammation Mediators metabolism, Macrophages, Peritoneal enzymology, Macrophages, Peritoneal immunology, Male, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Middle Aged, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Pregnancy, Signal Transduction, Streptozocin, Mice, Anti-Inflammatory Agents pharmacology, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Type 1 drug therapy, Docosahexaenoic Acids pharmacology, Inflammation drug therapy, Macrophage Activation drug effects, Macrophages, Peritoneal drug effects, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Nitric Oxide Synthase Type II metabolism
- Abstract
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic β-cell destruction and hyperglycemia. While monocytes and NOD-like receptor family-pyrin domain containing 3 (NLRP3) are associated with T1D onset and development, the specific receptors and factors involved in NLRP3 inflammasome activation remain unknown. Herein, we evaluated the inflammatory state of resident peritoneal macrophages (PMs) from genetically modified non-obese diabetic (NOD), NLRP3-KO, wild-type (WT) mice and in peripheral blood mononuclear cells (PBMCs) from human T1D patients. We also assessed the effect of docosahexaenoic acid (DHA) on the inflammatory status. Macrophages from STZ-induced T1D mice exhibited increased inflammatory cytokine/chemokine levels, nitric oxide (NO) secretion, NLRP3 and iNOS protein levels, and augmented glycolytic activity compared to control animals. In PMs from NOD and STZ-induced T1D mice, DHA reduced NO production and attenuated the inflammatory state. Furthermore, iNOS and IL-1β protein expression levels and NO production were lower in the PMs from diabetic NLRP3-KO mice than from WT mice. We also observed increased IL-1β secretion in PBMCs from T1D patients and immortalized murine macrophages treated with advanced glycation end products and palmitic acid. The present study demonstrated that the resident PMs are in a proinflammatory state characterized by increased NLRP3/iNOS pathway-mediated NO production, up-regulated proinflammatory cytokine/chemokine receptor expression and altered glycolytic activity. Notably, ex vivo treatment with DHA reverted the diabetes-induced changes and attenuated the macrophage inflammatory state. It is plausible that DHA supplementation could be employed as adjuvant therapy for treating individuals with T1D., (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2021
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