BACKGROUND: ABCA1 is known to suppress proinflammatory cytokines. RESULTS: ABCA1 activates PKA and up-regulates anti-inflammatory cytokine IL-10. Elevated PKA transforms macrophages to M2-like phenotype. Disrupting lipid rafts by statins MCD, and filipin recuperates ABCA1 phenotype and likely functions downstream of ABCA1. CONCLUSION: By modulating cholesterol, ABCA1 activates PKA. This generates M2-like macrophages. SIGNIFICANCE: ABCA1 does not simply suppress inflammatory response. It promotes M2-like activation and facilitates resolution. Nonresolving inflammatory response from macrophages is a major characteristic of atherosclerosis. Macrophage ABCA1 has been previously shown to suppress the secretion of proinflammatory cytokine. In the present study, we demonstrate that ABCA1 also promotes the secretion of IL-10, an anti-inflammatory cytokine critical for inflammation resolution. ABCA1(+/+) bone marrow-derived macrophages secrete more IL-10 but less proinflammatory cytokines than ABCA1(-/-) bone marrow-derived macrophages, similar to alternatively activated (M2) macrophages. We present evidence that ABCA1 activates PKA and that this elevated PKA activity contributes to M2-like inflammatory response from ABCA1(+/+) bone marrow-derived macrophages. Furthermore, cholesterol lowering by statins, methyl-β-cyclodextrin, or filipin also activates PKA and, consequently, transforms macrophages toward M2-like phenotype. Conversely, cholesterol enrichment suppresses PKA activity and promotes M1-like inflammatory response. As the primary function of ABCA1 is cholesterol removal, our results suggest that ABCA1 activates PKA by regulating cholesterol. Indeed, forced cholesterol enrichment in ABCA1-expressing macrophages suppresses PKA activation and elicits M1-like response. Collectively, these findings reveal a novel protective process by ABCA1-activated PKA in macrophages. They also suggest cholesterol lowering in extra-hepatic tissues by statins as an anti-inflammation strategy.
BACKGROUND:ABCA1 is known to suppress proinflammatory cytokines. RESULTS:ABCA1 activates PKA and up-regulates anti-inflammatory cytokine IL-10. Elevated PKA transforms macrophages to M2-like phenotype. Disrupting lipid rafts by statins MCD, and filipin recuperates ABCA1 phenotype and likely functions downstream of ABCA1. CONCLUSION: By modulating cholesterol, ABCA1 activates PKA. This generates M2-like macrophages. SIGNIFICANCE: ABCA1 does not simply suppress inflammatory response. It promotes M2-like activation and facilitates resolution. Nonresolving inflammatory response from macrophages is a major characteristic of atherosclerosis. Macrophage ABCA1 has been previously shown to suppress the secretion of proinflammatory cytokine. In the present study, we demonstrate that ABCA1 also promotes the secretion of IL-10, an anti-inflammatory cytokine critical for inflammation resolution. ABCA1(+/+) bone marrow-derived macrophages secrete more IL-10 but less proinflammatory cytokines than ABCA1(-/-) bone marrow-derived macrophages, similar to alternatively activated (M2) macrophages. We present evidence that ABCA1 activates PKA and that this elevated PKA activity contributes to M2-like inflammatory response from ABCA1(+/+) bone marrow-derived macrophages. Furthermore, cholesterol lowering by statins, methyl-β-cyclodextrin, or filipin also activates PKA and, consequently, transforms macrophages toward M2-like phenotype. Conversely, cholesterol enrichment suppresses PKA activity and promotes M1-like inflammatory response. As the primary function of ABCA1 is cholesterol removal, our results suggest that ABCA1 activates PKA by regulating cholesterol. Indeed, forced cholesterol enrichment in ABCA1-expressing macrophages suppresses PKA activation and elicits M1-like response. Collectively, these findings reveal a novel protective process by ABCA1-activated PKA in macrophages. They also suggest cholesterol lowering in extra-hepatic tissues by statins as an anti-inflammation strategy.
Authors: L J Pinderski Oslund; C C Hedrick; T Olvera; A Hagenbaugh; M Territo; J A Berliner; A I Fyfe Journal: Arterioscler Thromb Vasc Biol Date: 1999-12 Impact factor: 8.311
Authors: Lihua Lai; Kathleen M Azzam; Wan-Chi Lin; Prashant Rai; Julie M Lowe; Kristin A Gabor; Jennifer H Madenspacher; Jim J Aloor; John S Parks; Anders M Näär; Michael B Fessler Journal: J Biol Chem Date: 2016-07-28 Impact factor: 5.157
Authors: Kai Yin; Yong You; Vicki Swier; Lin Tang; Mohamed M Radwan; Amit N Pandya; Devendra K Agrawal Journal: Arterioscler Thromb Vasc Biol Date: 2015-09-17 Impact factor: 8.311
Authors: Leon M Tai; Shivesh Ghura; Kevin P Koster; Vaiva Liakaite; Mark Maienschein-Cline; Pinal Kanabar; Nicole Collins; Manel Ben-Aissa; Arden Zhengdeng Lei; Neil Bahroos; Stefan J Green; Bill Hendrickson; Linda J Van Eldik; Mary Jo LaDu Journal: J Neurochem Date: 2015-03-18 Impact factor: 5.372