Suppressor of cytokine signalling three regulated intestinal epithelial cell turnover : impact on microbial resistance

Shaw, Elisabeth and Else, Kathryn and Rigby, Rachael (2014) Suppressor of cytokine signalling three regulated intestinal epithelial cell turnover : impact on microbial resistance. In: UNSPECIFIED.

Abstract

Background: Intestinal epithelial cell (IEC) turnover has been implicated in the expulsion of and resistance to intestinal pathogens, including the murine whipworm Trichuris muris. Failure to initiate a transient increase in IEC turnover can lead to chronic infection. Over-expression of SOCS3 in vitro leads to decreased proliferation and reciprocally, lack of epithelial SOCS3 promotes proliferation and tumour growth in intestinal injury and cancer models. SOCS3 may have an important role in regulating the magnitude and/or duration of IEC turnover and consequently resistance to pathogens. This study aims to examine the ability of SOCS3 to regulate IEC turnover in an in vivo murine model of T. muris infection. Methods: SOCS3 expression was examined in the intestine of T. muris resistant or susceptible mice by immunohistochemistry and real-time PCR. Mice with and without IEC SOCS3 conditional knockdown were infected with T. muris and intestinal tissue examined at 3, 14, 21 and 35 days after infection. Crypt depth was measured and cell proliferation rates determined using an EdU assay. Outcome of infection was assessed at 35 days. Results: SOCS3 mRNA was increased in the intestine of mice susceptible to T. muris infection compared to resistant mice both prior to infection and at 14 days following infection. IEC SOCS3 protein was increased in susceptible mice at 15 and 21 days post-infection. This led to the hypothesis that increased SOCS3 blocks IEC turnover and a reduction in IEC SOCS3 expression may promote IEC proliferation and expulsion of parasites. Examination of tissue from IEC SOCS3 knockout mice, three days post infection, showed little difference in crypt depth or inflammation but suggested an increase in cell turnover, i.e. proliferation. It was too early to determine the impact of lack of IEC SOCS3 on helminth expulsion but this will be determined from later time points. Conclusion: During the early stages of helminth infection SOCS3 may be blocking proliferation as suggested by data from susceptible mice and preliminary knockout experiments. Lack of IEC SOCS3 may promote resistance to T. muris infection.