T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract

Abstract

Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103(+)CD11b(+) dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9(+) memory T helper type 1 (T(H)1) cells which activates the macrophages. IL-12 also caused some T(H)1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (T(H)1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9(+) T(H)1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a T(H)1 immune-mediated disease and identify potential targets for disease monitoring and therapy.

Impact of CCR7 on the gastrointestinal field effect

“…The attenuation of the FE through lack of CCR7 is consistent with our findings that the prolonged POI is based on an interaction of dendritic cells with T H 1 cells since the main function of CCR7 is to guide these key cells of the adaptive immune system toward each other for interactions (76,77). We described the role of the adaptive immune system in the FE for the first time (20).…”

“…Previously, we could show a recruitment of CD11bϩCD103ϩ dendritic cells into the intestinal muscularis, but not into the colonic muscularis after IM, which induced a T H 1 response by producing IL-12 at the manipulated site. These activated TH1 cells amplify the on-site inflammation by inducing the macrophage activation and migrate to unmanipulated gastrointestinal segments, such as the colon, where they also induce an inflammatory response (20). The interaction of activated dendritic cells with T cells is mainly directed by CCR7.…”

“…We showed that IM activates a memory T H 1 cell response via IL-12 produced by activated dendritic cells (20). These T H 1 cells are responsible for the dissemination of the POI over the entire intestinal tract, the FE.…”

“…We observed recruitment, activation, maturation, and migration of dendritic cells into the inflamed muscularis layer of the manipulated jejunum. These dendritic cells also interact with naive T cells in vitro (20,47). An important chemokine receptor for the migration and interaction of dendritic cells and T cells in peripheral tissue and secondary lymphoid tissues is CCR7.…”

Commensal bacterial internalization by epithelial cells: An alternative portal for gut leakiness

“…Disruption of the gut barrier, followed by penetration of microbial products into the gut mucosa and circulatory bloodstream, predisposes the host to enterocolitis, systemic inflammation, or septic complications. 2,3 Abnormal bacterial adherence and internalization by epithelial cells has been reported in patients and experimental models with colorectal cancers, [4][5][6] inflammatory bowel disease (IBD), 7,8 celiac disease, 9,10 chronic psychological stress, 11,12 surgical manipulation, 13 intestinal obstruction, 14,15 and antibiotic-resistant bacterial infection. 16 Recent evidence suggests that mucosa-associated bacteria may contribute to pathological phenomena since many exhibit adherent and invasive characteristics, and are therefore termed 'pathobionts' (a commensal with the potential to cause disease; see review papers elsewhere).…”