TY - JOUR
T1 - Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue
AU - Ahmad, Faiyaz
AU - Chung, Youn Wook
AU - Tang, Yan
AU - Hockman, Steven C.
AU - Liu, Shiwei
AU - Khan, Yusuf
AU - Huo, Kevin
AU - Billings, Eric
AU - Amar, Marcelo J.
AU - Remaley, Alan T.
AU - Manganiello, Vincent C.
PY - 2016/6/20
Y1 - 2016/6/20
N2 - Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to 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 WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, IL1β and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B-/-mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B-/-mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT of PDE3B-/-mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE-/-/PDE3B-/-and LDLR-/-/PDE3B-/-mice compared to apoE-/-and LDL-R-/-mice, respectively. Obesity-induced changes in serum-cholesterol were blocked in PDE3B-/-mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue.
AB - Activation of inflammation in white adipose tissue (WAT), includes infiltration/expansion of WAT macrophages, contributes pathogenesis of obesity, insulin resistance, and metabolic syndrome. The inflammasome comprises an intracellular sensor (NLR), caspase-1 and the adaptor ASC. Inflammasome activation leads to 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 WAT prevents inflammasome activation by reducing expression of NLRP3, caspase-1, ASC, AIM2, TNFα, IL1β and proinflammatory genes. Following IP injection of lipopolysaccharide (LPS), serum levels of IL1β and TNFα were reduced in PDE3B-/-mice compared to WT. Activation of signaling cascades, which mediate inflammasome responses, were modulated in PDE3B-/-mice WAT, including smad, NFAT, NFkB, and MAP kinases. Moreover, expression of chemokine CCL2, MCP-1 and its receptor CCR2, which play an important role in macrophage chemotaxis, were reduced in WAT of PDE3B-/-mice. In addition, atherosclerotic plaque formation was significantly reduced in the aorta of apoE-/-/PDE3B-/-and LDLR-/-/PDE3B-/-mice compared to apoE-/-and LDL-R-/-mice, respectively. Obesity-induced changes in serum-cholesterol were blocked in PDE3B-/-mice. Collectively, these data establish a role for PDE3B in modulating inflammatory response, which may contribute to a reduced inflammatory state in adipose tissue.
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U2 - 10.1038/srep28056
DO - 10.1038/srep28056
M3 - Article
C2 - 27321128
AN - SCOPUS:84975492597
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 28056
ER -
