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FoxOs promote apoptosis of insulin resistant macrophages during cholesterol-induced ER stress

¹Departments of Medicine, and
²Anatomy & Cell Biology and Physiology & Cellular Biophysics, Columbia University, New York, NY 10032, USA
³Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA

Objective: ER stress increases macrophage apoptosis, contributing to the complications of atherosclerosis. Insulin-resistant macrophages are more susceptible to ER stress-associated apoptosis probably contributing to macrophage death and necrotic core formation in atherosclerotic plaques in Type 2 diabetes. However the molecular mechanisms of increased apoptosis in insulin-resistant macrophages remain unclear.

Research Design and Methods: The studies were performed in insulin-resistant macrophages isolated from insulin receptor knock out or ob/ob mice. Gain- or loss-of function approaches were used to evaluate the rolls of FoxOs in ER stress-associated macrophage apoptosis.

Results: Insulin resistant macrophages showed attenuated Akt activation and increased nuclear localization of FoxO1 during ER stress induced by free cholesterol loading. Overexpression of active FoxO1 or FoxO3 failed to induce apoptosis in unchallenged macrophages, but exacerbated apoptosis in macrophages with an active ER stress response. Conversely, macrophages with genetic knock-outs of FoxO1, 3 and 4 were resistant to apoptosis in response to ER stress. FoxO1 was shown by ChIP and promoter expression analysis to induce IB gene expression and thereby to attenuate the increase of nuclear p65 and NF-B activity during ER stress, with pro-apoptotic and anti-inflammatory consequences.

Conclusions: Decreased Akt and increased FoxO transcription factor activity during the ER stress response leads to increased apoptosis of insulin resistant macrophages. FoxOs may have a dual cellular function, resulting in either pro-apoptotic or anti-inflammatory effects in an ER stress-modulated manner. In the complex plaque milieu the ultimate effect is likely to be an increase in macrophage apoptosis, plaque inflammation and destabilization.

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