Disorders in enteric bacteria recognition by intestinal macrophages (Mφ) are strongly correlated with the pathogenesis of chronic colitis; however the precise mechanisms remain unclear. The aim of the current study was to elucidate the roles of Mφ in intestinal inflammation by using an IL-10-deficient (IL-10−/−) mouse colitis model. GM-CSF-induced bone marrow-derived Mφ (GM-Mφ) and M-CSF-induced bone marrow-derived Mφ (M-Mφ) were generated from bone marrow CD11b+ cells. M-Mφ from IL-10−/− mice produced abnormally large amounts of IL-12 and IL-23 upon stimulation with heat-killed whole bacteria Ags, whereas M-Mφ from wild-type (WT) mice produced large amounts of IL-10 but not IL-12 or IL-23. In contrast, IL-12 production by GM-Mφ was not significantly different between WT and IL-10−/− mice. In ex vivo experiments, cytokine production ability of colonic lamina propria Mφ (CLPMφ) but not splenic Mφ from WT mice was similar to that of M-Mφ, and CLPMφ but not splenic Mφ from IL-10−/− mice also showed abnormal IL-12p70 hyperproduction upon stimulation with bacteria. Surprisingly, the abnormal IL-12p70 hyperproduction from M-Mφ from IL-10−/− mice was improved by IL-10 supplementation during the differentiation process. These results suggest that CLPMφ and M-Mφ act as anti-inflammatory Mφ and suppress excess inflammation induced by bacteria in WT mice. In IL-10−/− mice, however, such Mφ subsets differentiated into an abnormal phenotype under an IL-10-deficient environment, and bacteria recognition by abnormally differentiated subsets of intestinal Mφ may lead to Th1-dominant colitis via IL-12 and IL-23 hyperproduction. Our data provide new insights into the intestinal Mφ to gut flora relationship in the development of colitis in IL-10−/− mice.

[1] A numerical model incorporating experimentally determined fracture surface geometries and fracture permeability is proposed for characterizing aperture structures and fluid flow through rock fractures under confining pressures. The model was applied to artificially created granite tensile fractures with varying shear displacements (0-10 mm) and confining pressures (10-100 MPa). The findings of the study were consistent with those obtained previously, which characterized experimentally determined contact areas and changes in shear stress during the shear process. While the confining pressures considered herein are higher than those of previous studies, experimentally obtained fracture permeability is important for understanding subsurface flow, specifically the fluid flow characteristics in aperture structures under different confining pressures. Development of preferential flow paths is observed in all aperture structures, suggesting that the concept of channeling flow is applicable even under high confining pressures, as well as the existence of 3-D preferential flow paths within the subsurface fracture network.

Shear (Mode II) fractures with shear displacements of 1 and 5 mm were generated by direct shear on granite under normal stresses of 1, 20, and 60 MPa. Fracture surface mapping showed that the surface roughnesses of the shear fractures decreased with increasing shear displacement and normal stress and were smaller than those of tensile fractures reported in our previous study. Fluid flow experiments on the shear fractures provided fracture permeabilities at a wide range of confining pressures of 10–100 MPa. Nonmonotonic permeability was usually observed to decrease with increasing confining pressure. However, the permeability changes were different between the shear fractures generated at the normal stress of ≤20 and 60 MPa. In addition, obvious permeability changes with shear displacement were observed for 60 MPa, whereas no significant difference was observed for ≤20 MPa. Comparing the shear fractures with the tensile fractures having shear displacements revealed clear differences, even for equivalent shear displacements. Numerical models that were constructed using the data of the fracture surface mapping by matching their permeabilities with the experimentally evaluated fracture permeabilities revealed the development of preferential flow paths, i.e., channeling flows, for the shear fractures, providing a diversity of channeling flow in heterogeneous aperture distributions of rock fractures in the Earth's crust.

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