The Role of Suppressor of Cytokine Signalling 3 (SOCS3) in the Regulation of Intestinal Epithelial Cell Turnover in a Helminth Model

Abstract

Gastrointestinal epithelial cells (IEC) act as a first line of defence against invading pathogens and are replenished every 4‐5 days. An increase in IEC turnover aids the expulsion of intestinal pathogens including helminth infection. SOCS3 limits IEC proliferation with its loss associated with hyperproliferation and increased tumour growth in intestinal injury and cancer models. This study investigates SOCS3 effects on IEC turnover, outcome of infection and biochemical changes in response to infection in an in vivo Trichuris muris model.Mice with IEC SOCS3 conditional knockdown and controls were infected with T. muris. Crypt depth, cell proliferation rates, worm burden and immune response were assessed. Protein expression assessed by western blotting or immunohistochemistry.Increased SOCS3 expression was observed in cecum of T. muris susceptible vs. resistant mice strains. This supported our hypothesis that increased SOCS3 may limit IEC turnover and parasite expulsion. IEC deletion of SOCS3 did not lead to resistance to infection although a trend towards increased expulsion, compared to controls, was observed. At 35 days post infection an increase in proliferation of cells in cecal crypts was observed with no change in crypt depth in knockdown animals, supporting an increase in cell turnover. No difference in crypt dynamics was apparent in early stages of T. muris infection. Loss of SOCS3 was associated with altered indoleamine 2,3‐dioxygenase (IDO) expression in goblet cells.During parasitic challenge SOCS3 modulates IEC proliferation, potentially via a mechanism mediated though altered IDO.Medical Research Council G1100211/1