Namiko Hoshi

Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages

An interleukin controls a metabolic switch in macrophages that inhibits a signaling pathway, thereby suppressing intestinal inflammation. A way to switch off IBD Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohns disease are associated with defective interleukin-10 (IL-10) signaling. Although IL-10 plays an essential role in the control and resolution of inflammation, the mechanisms responsible for its anti-inflammatory actions remain unclear. Ip et al. show that in response to inflammation, IL-10 controls cellular metabolism in macrophages by inducing the mTOR inhibitor DDIT4 and preventing glucose uptake (see the Perspective by Kabat and Pearce). In mouse models and patient samples, defective IL-10 promoted accumulation of damaged macrophages and exacerbated inflammatory signals. Targeting mTORC1 thus might help to treat IBD and related disorders. Science, this issue p. 513; see also p. 488 Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1β.

MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10 deficient mice

Commensal bacterial sensing by Toll-like receptors (TLRs) is critical for maintaining intestinal homeostasis, but can lead to colitis in the absence of IL-10. While TLRs are expressed in multiple cell types in the colon, the cell type(s) responsible for the development of colitis currently unknown. Here, we generated mice that are selectively deficient in MyD88 in various cellular compartments in an IL-10−/− setting. While epithelial expression of MyD88 was dispensable, MyD88 expression in the mononuclear phagocyte (MNP) compartment was required for colitis development. Specifically, phenotypically distinct populations of colonic MNPs expressed high levels IL-1β, IL-23 and IL-6 and promoted Th17 responses in the absence of IL-10. Thus, gut bacterial sensing through MyD88 in MNPs drives inflammatory bowel disease (IBD) when unopposed by IL-10.

T cell-intrinsic role of IL-6 signaling in primary and memory responses

Innate immune recognition is critical for the induction of adaptive immune responses; however the underlying mechanisms remain incompletely understood. In this study, we demonstrate that T cell-specific deletion of the IL-6 receptor α chain (IL-6Rα) results in impaired Th1 and Th17 T cell responses in vivo, and a defect in Tfh function. Depletion of Tregs in these mice rescued the Th1 but not the Th17 response. Our data suggest that IL-6 signaling in effector T cells is required to overcome Treg-mediated suppression in vivo. We show that IL-6 cooperates with IL-1β to block the suppressive effect of Tregs on CD4+ T cells, at least in part by controlling their responsiveness to IL-2. In addition, although IL-6Rα-deficient T cells mount normal primary Th1 responses in the absence of Tregs, they fail to mature into functional memory cells, demonstrating a key role for IL-6 in CD4+ T cell memory formation. DOI: http://dx.doi.org/10.7554/eLife.01949.001

Feasibility and safety of endoscopic submucosal dissection for large colorectal tumors.

Purpose: Recently, endoscopic submucosal dissection (ESD) has been applied for superficial colorectal neoplasms and the number of publications about it has been increasing, but little is known about the outcomes of colorectal ESD for the lesions >50 mm. In this study, we evaluated the feasibility and safety of colorectal ESD for the lesions >50 mm compared with the lesions <50 mm. Methods: A total of 674 superficial colorectal neoplasms in 629 patients treated by ESD at Kobe University Hospital from July 2008 to July 2013 were included in the analysis. Results: The median operation time (range) in the large lesion group (≥5 cm) was 109 (37 to 596) minutes, and it was 55 (6 to 248) minutes in the small lesion group (<5 cm). Median procedure speed (range) in the large lesion group was 0.28 (0.06 to 0.83) cm2/min, and it was 0.19 (0.04 to 0.83) cm2/min in the small lesion group. The en bloc resection rate and the curative resection rate in the small lesion group was 98.7% and 96.0%, and those were 95.7% and 91.4% in the large lesion group, respectively. In terms of adverse events, perforation, muscle damage, and postoperative bleeding occurred at similar frequency in both groups. Conclusions: ESD on colorectal lesions >50 mm takes longer operation time; however, it is resected time effectively without increasing the risk of adverse events compared with smaller lesions by ESD.

Esophageal diverticulum exposed during endoscopic submucosal dissection of superficial cancer.

Endoscopic submucosal dissection (ESD) is now widely accepted as a strategy to treat superficial esophageal neoplasms. The rate of adverse events, such as perforation, has been decreasing with the improvement of devices and techniques. In this paper, we report a case of esophageal cancer that had a diverticulum under cancerous epithelium. The diverticulum was not detected during preoperative examination, and led to perforation during the ESD procedure. Our case shows that, although rare, some diverticula can exist underneath the mucosal surface without obvious depression. If there is any sign of hidden diverticula during ESD, surgeons should proceed with caution or, depending on the case, the procedure should be discontinued to avoid adverse events.

Germs gone wild

The normally harmless behavior of bacteria in the intestinal tract is maintained by community structure and the integrity of host defenses. When either or both of these are compromised, a few disgruntled outcasts can cause a riot, taking down the whole neighborhood (pages 799-806).

42 Metabolome Analysis-Based Attempt to Discover Therapeutic Agents for Non-Alcoholic Steatohepatitis

G A A b st ra ct s acid (TCDCA), taurodeoxycholic acid (TDCA), tauroursodeoxycholic acid (TUDCA), taurocholic acid (TCA), and tauro-β-muricholic acid (T-β-MCA) differed between CYP7A1-tg and WT mice. T-β-MCA, an antagonist of FXR was significantly increased in intestine but not in liver of CYP7A1-tg mice, suggesting that the intestinal FXR signaling pathway is inhibited in CYP7A1-tg mice. In agreement with these metabolic alterations, qPCR analysis revealed partially inhibited intestinal FXR signaling pathway and induced intestinal fatty acid β-oxidation, which could contribute to the lower adiposity in CYP7A1-tg mice. Conclusion: This study suggests that enlarged bile acid pool and altered bile acid composition, notably reduced secondary bile acids and increased T-β-MCA in the intestine may partially inhibit intestinal FXR signaling without affecting hepatic FXR signaling and contribute to altered lipid homeostasis and resistance to HFD-induced fatty liver, diabetes and obesity.