Impaired resolution of DSS-induced colitis in mice lacking the glucocorticoid receptor in myeloid cells

Abstract

Inflammatory bowel disease (IBD) is a highly prevalent intestinal disorder for which no cure exists. Currently, the standard first-line treatment of IBD consists of systemic glucocorticoid (GC) application, even though therapy can be complicated by unresponsiveness or adverse effects. In view of the importance of macrophages and neutrophils for the pathogenesis of IBD we set out to define the relevance of these cell types as targets of GC using the mouse model of DSS-induced colitis. We found that the disease did not resolve in GRlysM mice lacking the GC receptor (GR) in myeloid cells after removal of the chemical insult. While clinical symptoms and tissue damage in the colon ameliorated again in GRflox mice, the disease further aggravated in GRlysM littermates. The observed difference coincided with an increased abundance of macrophages in inflammatory infiltrates in the colon of mutant mice whereas neutrophil and T cell numbers were similar. Concomitantly, systemic IL-6 secretion and mRNA levels of pro-inflammatory cytokines in the colon were elevated in GRlysM mice and gene expression of scavenger receptors and IL-10 was diminished. Taken together, our results reveal an important role of myeloid cells as targets of GC in DSS-induced colitis and probably in IBD in humans as well.

Adoptive transfer of Trichinella spiralis-activated macrophages can ameliorate both Th1- and Th2-activated inflammation in murine models

“…9). Our data correspond well with those of Leung et al ., who reported that M2 macrophages inhibited colitis in a dinitrobenzene sulfonic murine colitis model 82,83 . ARG1 was originally hypothesized to promote Th2-driven inflammation 84–86 .…”

New insights into the cell- and tissue-specificity of glucocorticoid actions

“… 66 In a model of colitis induced by dextran sulfate sodium (DSS) using the GR LysM- Cre mouse model, it was shown that GR signaling in myeloid cells is required to resolve inflammation. 67 GCs also upregulate the expression of CD163, a scavenger receptor that is a marker of alternatively activated macrophages, in human monocytes and macrophages 68 , 69 and increase the ability of human macrophages to engulf apoptotic cells via phagocytosis, thereby contributing to the resolution of inflammation. 70 , 71 …”

Active Vaccination With EMMPRIN-Derived Multiple Antigenic Peptide (161-MAP) Reduces Angiogenesis in a Dextran Sodium Sulfate (DSS)-Induced Colitis Model

“…Thus, the intestinal milieu was probably reflecting a resolution state, rather than a pro-inflammatory response with high cytokine concentrations, even if the inflammatory cells were still physically present in the microenvironment. Supporting our premise are studies of DSS-induced colonic tissue that show reduced cytokine production at the mRNA or protein levels in the resolution phase compared to the acute phase of inflammation (24–26).…”