Journal Article

GSTO1-1 plays a pro-inflammatory role in models of inflammation, colitis and obesity

Menon, Deepthi, Tummala, Padmaja, Walters, Michael A., Strasser, Jessica, Dahlstrom, Jane E., Dahlin, Jayme L., O’Neill, Luke A. J., Brüstle, Anne, Oakley, Aaron J., Innes, Ashlee, Board, Philip G., Rooke, Melissa, Baell, Jonathan B., Nguyen, Nghi, Casarotto, Marco G., Burgio, Gaetan, Jensen, Lora M., Xie, Yiyue, Cuellar, Matthew

2017

Overview

Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-inflammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct inflammatory disease models. GSTO1-1 deficiency ameliorates the inflammatory response stimulated by LPS and attenuates the inflammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 deficient mice show a more severe inflammatory response and increased escape of bacteria from the colon into the lymphatic system in a dextran sodium sulfate mediated model of inflammatory bowel disease. These responses are similar to those of TLR4 and MyD88 deficient mice in these models and confirm that GSTO1-1 is critical for a TLR4-like pro-inflammatory response in vivo . In wild-type mice, we show that a small molecule inhibitor that covalently binds in the active site of GSTO1-1 can be used to ameliorate the inflammatory response to LPS. Our findings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of inflammation and suggest their possible application in the treatment of a range of inflammatory conditions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/6 / 13 / 13/21 / 631/154 / 64 / 64/60 / 692/308/1426 / Animal models / Animals / Carrier Proteins - genetics / Carrier Proteins - metabolism / Colitis / Colitis - drug therapy / Colitis - genetics / Colitis - metabolism / Colon / Dextran / Glucose tolerance / Glutathione transferase / Glutathione Transferase - genetics / Glutathione Transferase - metabolism / High fat diet / Humanities and Social Sciences / Inflammation - drug therapy / Inflammation - genetics / Inflammation - metabolism / Inflammatory bowel diseases / Insulin / Intestine / Lipopolysaccharides / Lymphatic system / Male / Mice / Mice, Inbred C57BL / multidisciplinary / MyD88 protein / Myeloid Differentiation Factor 88 - genetics / Myeloid Differentiation Factor 88 - metabolism / Obesity - drug therapy / Obesity - genetics / Obesity - metabolism / Rodents / Science / Science (multidisciplinary) / Small Molecule Libraries - therapeutic use / Sodium / Sodium sulfate / Sulfates / TLR4 protein / Toll-Like Receptor 4 - genetics / Toll-Like Receptor 4 - metabolism / Toll-like receptors