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

Journal Article


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Abstract


  • Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-infammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct infammatory disease models. GSTO1-1 defciency ameliorates the inflammatory response stimulated by LPS and attenuates the infammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 defcient 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 infammatory bowel disease. These responses are similar to those of TLR4 and MyD88 defcient mice in these models and confrm that GSTO1-1 is critical for a TLR4-like pro-infammatory 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 infammatory response to LPS. Our fndings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of infammation and suggest their possible application in the treatment of a range of inflammatory conditions.

Authors


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

Publication Date


  • 2017

Citation


  • Menon, D., Innes, A., Oakley, A. J., Dahlstrom, J. E., Jensen, L. M., Brustle, A., Tummala, P., Rooke, M., Casarotto, M. G., Baell, J. B., Nguyen, N., Xie, Y., Cuellar, M., Strasser, J., Dahlin, J. L., Walters, M. A., Burgio, G., O'Neill, L. A. J. & Board, P. G. (2017). GSTO1-1 plays a pro-inflammatory role in models of inflammation, colitis and obesity. Scientific Reports, 7 17832-17832.

Scopus Eid


  • 2-s2.0-85038625545

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=6199&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/5146

Number Of Pages


  • 0

Start Page


  • 17832

End Page


  • 17832

Volume


  • 7

Place Of Publication


  • United Kingdom

Abstract


  • Glutathione transferase Omega 1 (GSTO1-1) is an atypical GST reported to play a pro-infammatory role in response to LPS. Here we show that genetic knockout of Gsto1 alters the response of mice to three distinct infammatory disease models. GSTO1-1 defciency ameliorates the inflammatory response stimulated by LPS and attenuates the infammatory impact of a high fat diet on glucose tolerance and insulin resistance. In contrast, GSTO1-1 defcient 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 infammatory bowel disease. These responses are similar to those of TLR4 and MyD88 defcient mice in these models and confrm that GSTO1-1 is critical for a TLR4-like pro-infammatory 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 infammatory response to LPS. Our fndings demonstrate the potential therapeutic utility of GSTO1-1 inhibitors in the modulation of infammation and suggest their possible application in the treatment of a range of inflammatory conditions.

Authors


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

Publication Date


  • 2017

Citation


  • Menon, D., Innes, A., Oakley, A. J., Dahlstrom, J. E., Jensen, L. M., Brustle, A., Tummala, P., Rooke, M., Casarotto, M. G., Baell, J. B., Nguyen, N., Xie, Y., Cuellar, M., Strasser, J., Dahlin, J. L., Walters, M. A., Burgio, G., O'Neill, L. A. J. & Board, P. G. (2017). GSTO1-1 plays a pro-inflammatory role in models of inflammation, colitis and obesity. Scientific Reports, 7 17832-17832.

Scopus Eid


  • 2-s2.0-85038625545

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=6199&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/5146

Number Of Pages


  • 0

Start Page


  • 17832

End Page


  • 17832

Volume


  • 7

Place Of Publication


  • United Kingdom