ER Stress Promotes Inflammation through Re-wIREd Macrophages in Obesity  Benjamin P. Garfinkel, Gökhan S. Hotamisligil  Molecular Cell  Volume 66, Issue 6, Pages 731-733 (June 2017) DOI: 10.1016/j.molcel.2017.05.037 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 Context-Dependent Effects of IRE1α Inhibition Recent studies have shown that the metabolic effects of IRE1α activity are tissue and context dependent, and can be either detrimental (blue shading) or beneficial (red shading). In adipose tissue macrophages (top left), nutrient overload activates IRE1α, leading to increased M1 polarization and inflammation, alongside decreased M2 polarization and impaired thermogenesis, collectively resulting in metabolic dysfunction (Shan et al., 2017). Similarly, in the vascular endothelium (top right), nutrient overload activates IRE1α, stimulating the NLRP3 inflammasome and increasing macrophage recruitment to atherosclerotic lesions (Tufanli et al., 2017). In the type 1 diabetic pancreas (bottom right), IRE1α activation by ABL kinases leads to increased apoptosis and disease progression (Morita et al., 2017), while in the healthy pancreas, IRE1α activity is necessary for normal insulin synthesis and secretion (Hassler et al., 2015). Finally, in the liver (bottom left), nutrient-induced inflammation in obesity activates iNOS, leading to inactivation of IRE1α RNase activity, disproportionate kinase activity, maladaptive signaling including JNK activation, insulin resistance, and glucose intolerance (Yang et al., 2015). Molecular Cell 2017 66, 731-733DOI: (10.1016/j.molcel.2017.05.037) Copyright © 2017 Elsevier Inc. Terms and Conditions