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

Abstract

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.

CP‐25 exerts therapeutic effects in mice with dextran sodium sulfate‐induced colitis by inhibiting GRK2 translocation to downregulate the TLR4‐NF‐κB‐NLRP3 inflammasome signaling pathway in macrophages

“…All these data indicate that GRK2 plays a key role in inflammatory immune disease. A previous study showed that GRK2 deficiency protected mice from DSS‐induced colitis 16 . The current study highlights the important role of GRK2 in mediating colitis and suggests that GRK2 might be a potential drug target for IBD.…”

“…Changes in GRK2 levels and functions play a key role in the progression of certain diseases 53,54 . The GRK2 level was related to the degree of inflammation in UC patients and animal disease models 16,55 . All these data indicate that GRK2 plays a key role in inflammatory immune disease.…”

“…53,54 The GRK2 level was related to the degree of inflammation in UC patients and animal disease models. 16,55 All these data indicate that GRK2 plays a key role in inflammatory immune disease. A previous study showed that GRK2 deficiency protected mice from DSS-induced colitis.…”

“…GRK2 deficiency protects mice from DSS‐induced colitis 16 . The deletion of GRK2 can inhibit the polarization of M1 macrophages and increase M2 macrophage polarization 17 .…”

“…15 GRK2 deficiency protects mice from DSS-induced colitis. 16 The deletion of GRK2 can inhibit the polarization of M1 macrophages and increase M2 macrophage polarization. 17 These studies indicate that GRK2 plays an important role in mediating inflammation and suggests that GRK2 might be a potential drug target for the treatment of IBD.…”