Abstract
IntroductionSuppressor of cytokine signaling 3 (SOCS3) is a tumour suppressor, limiting intestinal epithelial cell (IEC) proliferation in acute inflammation, and tumour growth, but little is known regarding its role in mucosal homeostasis. Resistance to the intestinal helminth Trichuris muris relies on an “epithelial escalator” to expel the parasite. IEC turnover is restricted by parasite‐induced indoleamine 2,3‐dioxygenase (IDO).MethodsMice with or without conditional knockout of SOCS3 were infected with T. muris. Crypt depth, worm burden, and proliferating cells and IDO were quantified. SOCS3 knockdown was also performed in human IEC cell lines.ResultsChronic T. muris infection increased expression of SOCS3 in wild‐type mice. Lack of IEC SOCS3 led to a modest increase in epithelial turnover. This translated to a lower worm burden, but not complete elimination of the parasite suggesting a compensatory mechanism, possibly IDO, as seen in SOCS3 knockdown.ConclusionsWe report that SOCS3 impacts on IEC turnover following T. muris infection, potentially through enhancement of IDO. IDO may dampen the immune response which can drive IEC hyperproliferation in the absence of SOCS3, demonstrating the intricate interplay of immune signals regulating mucosal homeostasis, and suggesting a novel tumour suppressor role of SOCS3.
Highlights
Suppressor of cytokine signaling 3 (SOCS3) is a tumour suppressor, limiting intestinal epithelial cell (IEC) proliferation in acute inflammation, and tumour growth, but little is known regarding its role in mucosal homeostasis
SOCS3 expression is increased in the intestine of mice susceptible to T. muris infection
IEC SOCS3 deficiency is associated with increased IEC turnover Mice deficient in IEC SOCS3 (HO-VC) and control homozygous littermates lacking the villin cre-recombinase transgene (HO-WT) were generated on the C57BL/6 background and infected with low dose T. muris
Summary
Suppressor of cytokine signaling 3 (SOCS3) is a tumour suppressor, limiting intestinal epithelial cell (IEC) proliferation in acute inflammation, and tumour growth, but little is known regarding its role in mucosal homeostasis. Intestinal epithelial cells (IEC) lining the gastrointestinal tract act as a first line of defence from the plethora of antigenic luminal content This epithelium is in a constant state of renewal and repair which must be balanced to maintain barrier function whilst avoiding excessive growth. MyD88-deficient and GF, mice are more susceptible to colonic injury, but do not develop spontaneous or carcinogen induced colonic tumours [1, 8,9,10] These contrasting findings highlight that epithelial cells, and our immune system, must balance beneficial and detrimental effects of commensal microflora and support the notion that TLR signaling permits repair and restitution, yet must be tightly regulated to protect against excessive repair which can lead to cancer. These data support our central hypothesis that SOCS3, which impacts upon multiple signaling pathways, is a key mediator of mucosal homeostasis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
