Dr John Worthington

John Worthington – Research summary

Dr John Worthington

Dr John Worthington

The intestinal epithelium represents one of the body’s most important interfaces with the external environment, not only as an essential point of detection and absorption of nutrients, but also acting as an efficient barrier against the plethora of toxins and microorganisms we encounter on a daily basis. Indeed, the intestinal epithelium offers the first interaction between pathogens and our body’s defences and as such harbors the major immune system of the body. The numerous cells that make up the protective epithelial barrier, such as absorptive enterocytes and secretory Paneth and goblet cells, have all been identified as playing a role in driving innate immune responses which ultimately impinge on adaptive protective immunity.

My research focuses on the often neglected enteroendocrine cells (EECs) of the epithelium, which despite only comprising 1% of the epithelium; collectively form the largest mammalian endocrine system. Regulatory peptides and amines are released from EECs in response to luminal nutrients, and have classically been studied in terms of their role in controlling feeding centres in the brain via stimulation of the vagus nerve. However, the possibility that they play a role in orchestrating the immune response remains largely overlooked. Indeed, recent studies have implicated a role for EECs in innate immunity as they possess functional Toll like receptors and alterations in EEC numbers and secretions are well associated with intestinal infections.

My work focuses on understanding the interactions between our gut’s endocrine and immune systems during homeostasis and inflammation. I utilize intestinal infection models as well as in vitro studies to dissect the mechanistic interaction between these diverse systems to potentially inform new EEC-derived therapeutic strategies for inflammatory diseases of the intestine.

Publications

  • J. J. Worthington, J.T. McLaughlin, R.K. Grencis (2013). Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion. Plos Pathogens. 9(1):e1003122.
  • J. J. Worthington, J. E. Klementowicz, S.Rahman, B.I. Czajkowska, H. Waldmann, T. Sparwasser, R.K. Grencis, M. A. Travis (2013). Loss of the TGFß-activating integrin avß8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity. Plos Pathogens. 9(10):e1003675.
  • J.J. Worthington, T.M. Fenton, B.I. Czajkowska, J.E. Klementowicz, M.A. Travis (2012). TGFß activation by dendritic cells: a crucial pathway during immune homoeostasis and inflammation. Immunobiology, 217, 1259-65.
  • J.J. Worthington, B.I. Czajkowska, A.C. Melton, M.A. Travis (2011). Intestinal dendritic cells specialize to activate TGFß and induce Foxp3+ T Regulatory Cells via integrin avß8. Gastroenterology, 141, 1802-12.
  • J.J. Worthington, J.E. Klementowicz, M.A. Travis (2011). TGFß: a sleeping giant awoken by integrins. Trends in Biochem. Sci. 36, 47-54.
  • G. W. Moran; F. C. Leslie; S. E. Levison; J.J. Worthington; J. T. McLaughlin (2008). Enteroendocrine cells: neglected players in gastrointestinal disorders? Therap Adv Gastroenterol. 1(1):51-60.

Publications

  • J. J. Worthington, J.T. McLaughlin, R.K. Grencis (2013). Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion. Plos Pathogens. 9(1):e1003122.
  • J. J. Worthington, J. E. Klementowicz, S.Rahman, B.I. Czajkowska, H. Waldmann, T. Sparwasser, R.K. Grencis, M. A. Travis (2013). Loss of the TGFß-activating integrin avß8 on dendritic cells protects mice from chronic intestinal parasitic infection via control of type 2 immunity. Plos Pathogens. 9(10):e1003675.
  • J.J. Worthington, T.M. Fenton, B.I. Czajkowska, J.E. Klementowicz, M.A. Travis (2012). TGFß activation by dendritic cells: a crucial pathway during immune homoeostasis and inflammation. Immunobiology, 217, 1259-65.
  • J.J. Worthington, B.I. Czajkowska, A.C. Melton, M.A. Travis (2011). Intestinal dendritic cells specialize to activate TGFß and induce Foxp3+ T Regulatory Cells via integrin avß8. Gastroenterology, 141, 1802-12.
  • J.J. Worthington, J.E. Klementowicz, M.A. Travis (2011). TGFß: a sleeping giant awoken by integrins. Trends in Biochem. Sci. 36, 47-54.
  • G. W. Moran; F. C. Leslie; S. E. Levison; J.J. Worthington; J. T. McLaughlin (2008). Enteroendocrine cells: neglected players in gastrointestinal disorders? Therap Adv Gastroenterol. 1(1):51-60.

Biography

After receiving my BSc in Biology from Nottingham University in 2002, I became a Research Technician in Professor Grencis' lab here at The University of Manchester. I soon became fascinated with host-parasite interactions of the enteric environment and after completing a short research technician post in endocrinology went on to pursue a PhD in 2004, under the supervision of Professor John McLaughlin. After receiving my PhD in 2008, entitled 'Molecular mechanisms of the gut immune systems and effects on nutrient sensing cells', I joined the lab of Dr Mark Travis in the Wellcome Trust Centre for Cell Matrix Research, examining the role of the integrin avß8 on dendritic cells during infection and autoimmunity. I followed Mark to the newly established Manchester Collaborative Centre for Inflammation Research in 2012 for a second post-doc, establishing an essential role for avß8 integrin on regulatory T cells during autoimmunity, before gaining a Wellcome Trust funded stepping stones fellowship to help establish my own lab.