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.

The synergistic use of ophthalmoscopy, flow cytometry, and immunofluorescence microscopy allows detailed dissection of the in vivo response of mononuclear phagocytes to laser injury of the fundus. The number of microGCs increased in the retina. DCs and MPhis were present in the retina and choroid infiltrate. MPhis and granulocytes persisted in the choroid infiltrate longer than previously thought.

CCR2 is thought to recruit monocytes to sites of infection. Two subpopulations of murine blood monocytes differing in Gr1 and CCR2 expression have been described. The exact role of CCR2 in migration of CCR2lowGr1low and CCR2highGr1high monocytes into nonlymphoid tissue is controversial. In this study, we have addressed this question in a murine model of bacterial urinary tract infection. Only Gr1high monocytes were recruited into the infected bladder. CCR2 deficiency reduced their frequency in this organ, indicating a requirement of this chemokine receptor. Importantly, CCR2-deficient mice also showed reduced Gr1high monocyte numbers in the blood, but not in the bone marrow (BM), indicating that CCR2 acted at the step of monocyte release into the circulation. The same was found also in noninfected mice, indicating a further involvement of CCR2 in steady-state BM egress. An additional requirement of CCR2 in monocyte recruitment from the blood into the bladder was excluded by tracking particle-labeled endogenous monocytes and by adoptive transfer of BM-derived monocyte subsets. These findings demonstrate that CCR2 governs homeostatic and infection-triggered release of Gr1high monocytes from the BM into the blood but is dispensable for recruitment into a nonlymphoid tissue.

The role of dendritic cells (DC) in urinary tract infections (UTI) is unknown. These cells contribute directly to the innate defense against various viral and bacterial infections. Here, we studied their role in UTI using an experimental model induced by transurethral instillation of the uropathogenic Escherichia coli (UPEC) strain 536 into C57BL/6 mice. While few DC were found in the uninfected bladder, many had been recruited after 24 h, mostly to the submucosa and uroepithelium. They expressed markers of activation and maturation and exhibited the CD11b tumor necrosis factor alpha (TNF-␣)-and inducible nitric oxide synthase (iNOS)-producing CD11bINT DC (Tip-DC) were detected, which recently were proposed to be critical in the defense against bacterial infections. However, Tip-DC-deficient CCR2 ؊/؊ mice did not show reduced clearance of UPEC from the infected bladder. Moreover, clearance was also unimpaired in CD11c-DTR mice depleted of all DC by injection of diphtheria toxin. This may be explained by the abundance of granulocytes and of iNOS-and TNF-␣-producing non-DC that were able to replace Tip-DC functionality. These findings demonstrate that some of the abundant DC recruited in UTI contributed innate immune effector functions, which were, however, dispensable in the microenvironment of the bladder.

Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune-mediated. The aim of this study was to investigate the role of secondary lymphoid organs [mesenteric lymph nodes (MLN), gut-associated lymphoid tissue (GALT)] in IM-mediated FE by employing mice with deficient secondary lymphoid organs (aly/aly, MLN ex) or by administration of 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720), an immunomodulating agent that inhibits emigration of lymphocytes out of lymphoid organs. Small bowel muscularis, and colonic muscularis from wild-type mice as control, from aly/aly mice, FTY720-treated mice (daily dose of 1.0 mg/kg mouse ip starting 3 days before surgical procedure), and wild-type mice that had undergone removal of mesenteric lymph nodes before IM (MLN ex mice) were obtained after selective IM of the jejunum or sham operation. FE was analyzed by measuring transit time of orally administered fluorescent dextran in the gastrointestinal tract [geometric center (GC) of fluorescent dextran], colonic transit time, infiltration of myeloperoxidase-positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1α] were determined by Taqman-PCR. We observed a significantly reduced upregulation of proinflammatory cytokines (IL-6, TNF-α, MIP-1α) in colonic muscularis of MLN ex mice, aly/aly mice, and FTY720-treated mice compared with wild-type mice. Contractility of circular muscularis strips of the colon but not the jejunum was significantly improved in aly/aly mice and FTY720-treated wild-type mice. Additionally, inflammation of the colon determined by the number of myeloperoxidase-positive cells and colonic transit time were significantly improved in aly/aly mice, FTY720-treated wild-type mice, and in MLN ex mice. In summary, lack of secondary lymphoid organs (MLN + GALT) in aly/aly mice or administration of FTY720 abrogated FE after IM as opposed to wild-type mice. These data demonstrate that secondary lymphoid organs are involved in the propagation of FE and postoperative ileus. FTY720 indirectly affects FE by inhibiting migration of activated T cells from the jejunum and adjacent secondary lymphoid organs to the colon. These findings support the crucial role of the adaptive immune system in FE, most likely by a sphyngosine 1-phosphate-dependent mechanism.