Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue

Faiyaz Ahmad, Youn Wook Chung, Yan Tang, Steven C. Hockman, Shiwei Liu, Yusuf Khan, Kevin Huo, Eric Billings, Marcelo J. Amar, Alan T. Remaley, Vincent C. Manganiello

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Abstract

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.

Original languageEnglish (US)
Article number28056
JournalScientific Reports
Volume6
DOIs
StatePublished - Jun 20 2016
Externally publishedYes

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Cite this

Ahmad, F., Chung, Y. W., Tang, Y., Hockman, S. C., Liu, S., Khan, Y., Huo, K., Billings, E., Amar, M. J., Remaley, A. T., & Manganiello, V. C. (2016). Phosphodiesterase 3B (PDE3B) regulates NLRP3 inflammasome in adipose tissue. Scientific Reports, 6, [28056]. https://doi.org/10.1038/srep28056