G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in mice

Background: Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation. Aim: To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis. Methods: Colitis was induced by administering 1% DSS in drinking water to GRK6−/−, GRK6+/− and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1β (IL1β), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6−/− mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay. Results: The severity of colitis was increased in GRK6−/− and GRK6+/− mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6−/− granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6−/− and GRK6+/− mice developed chronic colitis, which was accompanied by increased IL1β and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6−/− mice. Conclusions: The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.