KAG-308, a newly-identified EP4-selective agonist shows efficacy for treating ulcerative colitis and can bring about lower risk of colorectal carcinogenesis by oral administration.

Agonists for EP4 receptor, a prostaglandin E2 receptor subtype, appear to be a promising therapeutic strategy for ulcerative colitis (UC) due to their anti-inflammatory and epithelial regeneration activities. However, the clinical development of orally-available EP4 agonists for mild to moderate UC has not yet been reported. Furthermore, the possibility of an increased risk of colitis-associated cancer (CAC) through direct proliferative effects on epithelial cells via EP4 signaling has not been ruled out.

Classical Th1 cells obtain colitogenicity by co-existence of RORγt-expressing T cells in experimental colitis.

Background: Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (RORγt)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without RORγt expression in the pathogenesis of colitis remains poorly understood.

Cross-talk between RORγt+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease.

Background: Interleukin (IL)-22-producing RORγt innate lymphoid cells (ILCs) play a pivotal role in intestinal immunity. Recent reports demonstrated that ILCs contribute to mucosal protection and intestinal inflammation in mice. In humans, numbers of RORγt ILCs are significantly increased in the intestine of patients with Crohn's disease (CD), suggesting that ILCs may be associated with intestinal inflammation in CD.

Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice.

Intestinal lamina propria dendritic cells (LPDCs) in mice are known to extend dendrites between the intestinal epithelia and the luminal side when processing luminal antigens. We conducted intrarectal cell transfer experiments of bone marrow-derived dendritic cells (BMDCs) in mice to assess dendritic cell penetration of the intestine. Intrarectally administered GFP(+) BMDCs localized in the colonic LP within 3h and the spleen within 12h after administration.

Dysregulated balance of retinoid-related orphan receptor γt-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis.

Retinoid-related orphan receptor (ROR) γt-expressing and IL-22-producing NKp46(+) innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-γ and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORγt(+)IL-22(+) ILC22 cells were localized in Thy-1(high)SCA-1(high) and/or Thy-1(high)SCA-1(low) subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORγt-sufficient Rag-2(-/-) mice.

CCR9+ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis.

Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation.

CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice.

Almost all mice lacking specific molecules associated with regulatory T cells or barrier function develop intestinal inflammation in the colon, but not in the small intestine (SI). Therefore, intestinal homeostasis of the SI may be tightly controlled by other mechanisms. To determine the role of CCR9(+) plasmacytoid dendritic cells (pDCs) in intestinal homeostasis of the SI we transferred CD4(+)CD45RB(high) T cells into ccr9(-/-)×rag-2(-/-) mice.