The multifactorial etiology of inflammatory bowel disease (IBD), which consists of Crohn’s disease (CD) and ulcerative colitis (UC), has posed significant challenges in the development of treatment options for affected patients. IBD therapeutics including steroids and immunosuppressive agents are focused on controlling symptoms of inflammation rather than targeting specific molecules. Despite the development of biologics such as anti-TNF (infliximab), representing a shift in IBD therapeutics, about half of IBD patients do not respond or lose response over time to conventional and biologic therapies, thus leaving IBD patients no options but to undergo surgery to resect affected regions of the intestine. Fortunately, small-molecule Janus kinase (JAK) inhibitors have shown promising results in patients with IBD. In particular, the pan-JAK inhibitor tofacitinib has been approved for the treatment of moderate-to-severe UC. Despite its effectiveness in inducing a clinical response and maintaining remission in UC patients, little is known about which cells involved in gut homeostasis, including intestinal epithelial cells (IECs), are targeted. The aim of the work described in this dissertation is to elucidate if and how tofacitinib exerts its beneficial effects on IECs and epithelial barrier function.
Using IEC culture and human enteroids challenged with cytokine-induced barrier dysfunction, we show for the first time that tofacitinib can reduce barrier permeability through claudin-2 regulation and normalization of ZO-1 localization. Through cell culture and animal models we also show that the signaling and barrier defects associated with loss of activity of the IBD susceptibility gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), can be corrected by tofacitinib. Additionally, the compromised barrier function arising from disrupted crosstalk between macrophages and IECs induced by PTPN2 loss was also reversed by tofacitinib treatment in vivo and in vitro.
Overall, the data in this dissertation show that tofacitinib can protect barrier integrity in IECs and reverse the consequences caused by a genetic defect in PTPN2. These data reveal the need for more specific IBD treatments on an individual basis. Tofacitinib may serve as a more effective treatment for IBD patients with PTPN2 loss-of-function mutations, thus leading to longer periods of remission and better quality of life.