The Role of the Chaperone Grp94/Gp96 in the Intestinal Barrier and Innate Immune Functions

摘要

Heat shock proteins (HSPs) play an important role in innate immune function of the intestinal mucosa and in the barrier function of intestinal epithelial cells. Among the HSPs expressed in epithelial cells, as well as cells of the innate immune system is Grp94/Gp96. Differences in protein expression of Gp96 have been observed in patients with inflammatory bowel disease (IBD), suggesting that this chaperone may be important in this pathology. The role that Gp96 plays seems to be different depending on the cell type where it is expressed. In epithelial cells, Gp96 is recognized by pathogenic bacteria and allows bacterial invasion and translocation. Gp96 is also increased in the epithelium of patients with Crohn's disease (CD) when compared with healthy subjects. In macrophages, where it is absent in IBD patients, Gp96 plays important role in the regulation of pro-inflammatory cytokines and the functionality of several receptors, such as Toll-like receptors, whereas in dendritic cells it is involved in cell maturation. The therapeutic effect of Gp96 has been reported in animal models of disease, where its exogenous administration ameliorated colitis and reduced tumor growth and metastasis, and increased the survival of mice. Of interest, the efficacy of Gp96 as a therapeutic vaccine is currently being evaluated in clinical trials with modest antitumor effects. Given the increasing evidence of the potential therapeutic effect of this chaperone, in this review we will highlight the physiological role of Gp96, specifically in the gut mucosa, and discuss potential therapeutic approaches.