Treg donation of sIL-6R to promote intestinal integrity and repair

Abstract

Abstract IBD affects roughly 1.6 million US adults, with its prevalence increasing since the late 1990s. Characterized by unchecked intestinal inflammation, multiple proinflammatory cytokines including IL6 have been implicated as critical factors in this pathology. It has been established that EZH2 is a gene involved in the production of specific histone methyltransferase enzymes, as well as in the differentiation of Treg cells. The association between the Treg master transcription factor, Foxp3 and EZH2 results in the suppressive function of Tregs, with our previous work revealing impairment of this interaction under the influence of IL6 signaling in an inflamed intestinal setting. We investigated this further in a murine preventative T cell transfer model of colitis that involved injecting donor Treg cells that lacked IL6Ra, into immunocompromised mice. Histological scoring of the mice receiving the IL6Rko Tregs revealed a resolved inflammatory milieu and flow cytometric analysis of cells isolated from the spleens and MLNs showed increased Foxp3+ expression when compared to mice that received WT Tregs. Foxp3IL6Rako mice were subjected to a DSS model of colitis to further characterize the absence of the IL6R on Treg function in the intestinal milieu. Exacerbated signs of colitis were observed through histology and colon shortening of the conditional knockout mice when compared to their WT counterparts. We postulate that Tregs could be acting as a donor of sILR to promote intestinal integrity and healing. Further experiments will be conducted to define a role for the IL6R in the development of Foxp3+ cells, along with outlining the instrumental process of sIL6R donation in the intestinal milieu. Supported by Mayo Clinic Graduate School for Biomedical Sciences