G protein-coupled receptor kinase-2-deficient mice are protected from dextran sodium sulfate-induced acute colitis

G protein-coupled receptor kinase 2 (GRK2) is a serine/threonine kinase and plays a key role in different disease processes. Previously, we showed that GRK2 knockdown enhances wound healing in colonic epithelial cells. Therefore, we hypothesized that ablation of GRK2 would protect mice from dextran sodium sulfate (DSS)-induced acute colitis. To test this, we administered DSS to wild-type (GRK2^+/+) and GRK2 heterozygous (GRK^+/-) mice in their drinking water for 7 days. As predicted, GRK2^+/- mice were protected from colitis as demonstrated by decreased weight loss (20% loss in GRK2^+/+ vs. 11% loss in GRK2^+/-). lower disease activity index (GRK2^+/+ 9.1 vs GRK2^+/- 4.1), and increased colon lengths (GRK2^+/+ 4.7 cm vs GRK2^+/- 5.3 cm). To examine the mechanisms by which GRK2^+/- mice are protected from colitis, we investigated expression of inflammatory genes in the colon as well as immune cell profiles in colonic lamina propria, mesenteric lymph node, and in bone marrow. Our results did not reveal differences in immune cell profiles between the two genotypes. However, expression of inflammatory genes was significantly decreased in DSS-treated GRK2^+/- mice compared with GRK2^+/+. To understand the mechanisms, we generated myeloid-specific GRK2 knockout mice and subjected them to DSS-induced colitis. Similar to whole body GRK2 heterozygous knockout mice, myeloid-specific knockout of GRK2 was sufficient for the protection from DSS-induced colitis. Together our results indicate that deficiency of GRK2 protects mice from DSS-induced colitis and further suggests that the mechanism of this effect is likely via GRK2 regulation of inflammatory genes in the myeloid cells.