ABSTRACT
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.
Subject(s)
Carrier Proteins/metabolism , Colitis/metabolism , Glutathione Transferase/metabolism , Inflammation/metabolism , Obesity/metabolism , Animals , Carrier Proteins/genetics , Colitis/drug therapy , Colitis/genetics , Glutathione Transferase/genetics , Inflammation/drug therapy , Inflammation/genetics , Male , Mice , Mice, Inbred C57BL , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Obesity/drug therapy , Obesity/genetics , Small Molecule Libraries/therapeutic use , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolismABSTRACT
Moxidectin is under consideration for development as a treatment for human scabies. As some arthropods show decreased sensitivity to moxidectin relative to ivermectin, it was important to assess this for Sarcoptes scabieiIn vitro assays showed that the concentration of moxidectin required to kill 50% of mites was lower than that of ivermectin (0.5 µM versus 1.8 µM at 24 h; P < 0.0001). This finding provides further support for moxidectin as a candidate for the treatment of human scabies.
