Arginase impedes the resolution of colitis by altering the microbiome and metabolome.

Arginase 1 (Arg1), which converts l-arginine into ornithine and urea, exerts pleiotropic immunoregulatory effects. However, the function of Arg1 in inflammatory bowel disease (IBD) remains poorly characterized. Here, we found that Arg1 expression correlated with the degree of inflammation in intestinal tissues from IBD patients. In mice, Arg1 was upregulated in an IL-4/IL-13- and intestinal microbiota-dependent manner. Tie2-Cre Arg1fl/fl mice lacking Arg1 in hematopoietic and endothelial cells recovered faster from colitis than Arg1-expressing (Arg1fl/fl) littermates. This correlated with decreased vessel density, compositional changes in intestinal microbiota, diminished infiltration by myeloid cells, and an accumulation of intraluminal polyamines that promote epithelial healing. The proresolving effect of Arg1 deletion was reduced by an l-arginine-free diet, but rescued by simultaneous deletion of other l-arginine-metabolizing enzymes, such as Arg2 or Nos2, demonstrating that protection from colitis requires l-arginine. Fecal microbiota transfers from Tie2-Cre Arg1fl/fl mice into WT recipients ameliorated intestinal inflammation, while transfers from WT littermates into Arg1-deficient mice prevented an advanced recovery from colitis. Thus, an increased availability of l-arginine as well as altered intestinal microbiota and metabolic products accounts for the accelerated resolution from colitis in the absence of Arg1. Consequently, l-arginine metabolism may serve as a target for clinical intervention in IBD patients.

CD83 orchestrates immunity toward self and non-self in dendritic cells.

Dendritic cells (DCs) are crucial to balance protective immunity and autoimmune inflammatory processes. Expression of CD83 is a well-established marker for mature DCs, although its physiological role is still not completely understood. Using a DC-specific CD83-conditional KO (CD83ΔDC) mouse, we provide new insights into the function of CD83 within this cell type. Interestingly, CD83-deficient DCs produced drastically increased IL-2 levels and displayed higher expression of the costimulatory molecules CD25 and OX40L, which causes superior induction of antigen-specific T cell responses and compromises Treg suppressive functions. This also directly translates into accelerated immune responses in vivo. Upon Salmonella typhimurium and Listeria monocytogenes infection, CD83ΔDC mice cleared both pathogens more efficiently, and CD83-deficient DCs expressed increased IL-12 levels after bacterial encounter. Using the experimental autoimmune encephalomyelitis model, autoimmune inflammation was dramatically aggravated in CD83ΔDC mice while resolution of inflammation was strongly reduced. This phenotype was associated with increased cell influx into the CNS accompanied by elevated Th17 cell numbers. Concomitantly, CD83ΔDC mice had reduced Treg numbers in peripheral lymphoid organs. In summary, we show that CD83 ablation on DCs results in enhanced immune responses by dysregulating tolerance mechanisms and thereby impairing resolution of inflammation, which also demonstrates high clinical relevance.

Comparison of simplistic biofilm models for evaluating irrigating solutions.

OBJECTIVE: Many innovations have recently been implemented in the field of endodontics, often based on a variety of in-vitro/ex-vivo test setups. It was the goal of this research to compare different biofilm models for evaluating the effectiveness of rinsing solutions. METHOD AND MATERIALS: Three different models have been applied in this study, including petri dishes with nutrient medium, arrays of human dentin disks, and split bovine root segments. The susceptibility of biofilms formed by Enterococcus faecalis to commonly used endodontic irrigants was tested. RESULTS: While citric acid 3% did not show an inhibitory effect on solid medium, mean maximum inhibition areolae of 9.8 ±â€¯1.6 mm were found for sodium hypochlorite 3%. Fluorescein solution was shown to penetrate dentin tubules to a depth of 0.5 to 1 mm, indicating that the dentin tubules are not freely accessible, but clotted by E faecalis biofilms. Rinsing root canals with a combination of citric acid, hydrogen peroxide, chlorhexidine, and sodium hypochlorite removed bacterial biofilms from the dentin tubules only to a depth of 0.5 mm, while bacteria in deeper regions were not affected. CONCLUSION: Standard irrigating solutions inhibit bacterial growth; however, due to the morphology of the tooth, the effect of irrigating media is restricted to the root canal and the adjacent volume of dentin tubules. Results from standardizable diffusion tests seem not to be predictive for clinical performance of irrigating solutions.