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Phosphodiesterase 3B (PDE3B) Regulates NLRP3 Inflammasome and Metabolic Cross Talk in Adipose Tissue
Author(s) -
Khan Faiyaz Ahmad,
Chung Youn Wook,
Tang Yan,
Hockman Steven C,
Liu Steve,
Khan Yusuf,
Huo Kevin,
Amar Marcelo J,
Remaley Alan T,
Manganiello Vincent C
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1135.1
Subject(s) - inflammasome , ccr2 , adipose tissue , white adipose tissue , chemokine , proinflammatory cytokine , ccl2 , inflammation , adipose tissue macrophages , endocrinology , medicine , tlr4 , chemistry , chemokine receptor
Activation of inflammation in white adipose tissue (WAT) which includes infiltration/expansion of WAT macrophages contributes to pathogenesis of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. The inflammasome protein complex comprises an intracellular sensor (typically a Nod‐like receptor, NLR), caspase‐1 (a cysteine protease) and the adaptor ASC (apoptosis‐associated speck‐like protein). Inflammasome activation leads to the maturation of caspase‐1 and processing of IL1β contributing to many metabolic disorders and directing adipocytes to a more insulin‐resistant phenotype. Ablation of PDE3B in SVJ129 mice epididymal white adipose tissue (EWAT) prevents inflammasome activation by reducing the expressions of NLRP3, caspase‐1, ASC, interferon‐inducible protein AIM2, TNFα, IL1β and proinflammatory genes (i.e, cyclooxygenase2). Following IP (intraperitoneal) injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B−/− mice compared to WT. Moreover, chemokine (C‐C motif) ligand 2 (CCL2)/monocyte chemotactic protein‐1 (MCP‐1) and its receptor CCR2, which play an important role in the macrophage chemotaxis, were less highly expressed in EWAT of PDE3B−/− mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE−/−/PDE3B−/− and LDL‐R−/−/PDE3B−/− mice compared to apoE−/− and LDL‐R−/− mice, respectively. Collectively, these data establish a role for PDE3B in modulating the inflammatory response which may contribute to the decreased inflammatory state and reduced aortic plaque formation in PDE3B−/− mice. Support or Funding Information Supported by the NHLBI Intramural Research Program