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

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 LDL-R(−/−)/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.