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CD103+ CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis.

Wenzel UA, Jonstrand C, Hansson GC, Wick MJ - PLoS ONE (2015)

Bottom Line: Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria.The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology.These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology and the Mucosal Immunobiology and Vaccine Center (MIVAC), Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+ CD11b- DCs and increased CD103- CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon. CD103+ CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103- CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+ CD11b+ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.

No MeSH data available.


Related in: MedlinePlus

Inflammatory cytokines characterize the distal colon of a subgroup of colitic Muc2-/- mice.Saponin extracts of proximal, middle and distal colon were prepared and normalized to total protein concentration. Cytokine expression was analyzed by CBA (A, C- F) or ELISA (B, G). Each symbol represents an individual mouse and the solid line indicates the mean of each group. Symbols of the same color in Figs 3 and 4 and S1 Fig represent samples from the same colon segment of the same animal. Mice are segregated into colitic and non-colitic according to neutrophil influx into the colon LP in the respective colon segment. Data are pooled from 5 independent experiments that examined 27 mice. The distal colon panels to the right of the vertical bar show the same distal colon data as to the left of the bar except that the colitic mouse group is segregated into group “A” and “B”. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
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pone.0130750.g003: Inflammatory cytokines characterize the distal colon of a subgroup of colitic Muc2-/- mice.Saponin extracts of proximal, middle and distal colon were prepared and normalized to total protein concentration. Cytokine expression was analyzed by CBA (A, C- F) or ELISA (B, G). Each symbol represents an individual mouse and the solid line indicates the mean of each group. Symbols of the same color in Figs 3 and 4 and S1 Fig represent samples from the same colon segment of the same animal. Mice are segregated into colitic and non-colitic according to neutrophil influx into the colon LP in the respective colon segment. Data are pooled from 5 independent experiments that examined 27 mice. The distal colon panels to the right of the vertical bar show the same distal colon data as to the left of the bar except that the colitic mouse group is segregated into group “A” and “B”. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.

Mentions: To better understand the nature of the inflammation in Muc2-/- mice, we assessed the local cytokine environment and correlated it with the local cellular composition in the same colon segment of the same individual. To achieve this, the proximal, middle and distal colon segments were each divided in half and cytokines were quantified in one half, while cell populations were analyzed by flow cytometry in the remaining half. In general, inflammatory cytokine production increased from the proximal to distal colon (Fig 3A–3E), which was particularly apparent for IL-6. In the distal colon of colitic mice, the concentration of pro-inflammatory cytokines seemed to segregate the mice into subgroups (Fig 3, far right, groups “A” and “B”). That is, group B colitic mice had higher levels of IL-6, IL-1β, TNFα, IFN-γ and IL-17a together with significantly lower IL-10 in the distal colon. These same mice were regarded as colitic in all three sections of the colon except for one mouse (beige symbol), which did not have elevated neutrophils in the proximal colon (Figure A in S1 Fig). In contrast, group A colitic mice had either unchanged or reduced levels of the pro-inflammatory cytokines in the distal colon as well as reduced IL-10 (Fig 3A–3G, far right). Unlike group B mice, group A animals had increased neutrophil influx only in the distal colon (Figure A in S1 Fig and Fig 3). Thus, colitic mice can be divided into A and B subgroups based on cytokine profile in the distal colon and whether increased neutrophils has spread proximally.


CD103+ CD11b+ Dendritic Cells Induce Th17 T Cells in Muc2-Deficient Mice with Extensively Spread Colitis.

Wenzel UA, Jonstrand C, Hansson GC, Wick MJ - PLoS ONE (2015)

Inflammatory cytokines characterize the distal colon of a subgroup of colitic Muc2-/- mice.Saponin extracts of proximal, middle and distal colon were prepared and normalized to total protein concentration. Cytokine expression was analyzed by CBA (A, C- F) or ELISA (B, G). Each symbol represents an individual mouse and the solid line indicates the mean of each group. Symbols of the same color in Figs 3 and 4 and S1 Fig represent samples from the same colon segment of the same animal. Mice are segregated into colitic and non-colitic according to neutrophil influx into the colon LP in the respective colon segment. Data are pooled from 5 independent experiments that examined 27 mice. The distal colon panels to the right of the vertical bar show the same distal colon data as to the left of the bar except that the colitic mouse group is segregated into group “A” and “B”. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487685&req=5

pone.0130750.g003: Inflammatory cytokines characterize the distal colon of a subgroup of colitic Muc2-/- mice.Saponin extracts of proximal, middle and distal colon were prepared and normalized to total protein concentration. Cytokine expression was analyzed by CBA (A, C- F) or ELISA (B, G). Each symbol represents an individual mouse and the solid line indicates the mean of each group. Symbols of the same color in Figs 3 and 4 and S1 Fig represent samples from the same colon segment of the same animal. Mice are segregated into colitic and non-colitic according to neutrophil influx into the colon LP in the respective colon segment. Data are pooled from 5 independent experiments that examined 27 mice. The distal colon panels to the right of the vertical bar show the same distal colon data as to the left of the bar except that the colitic mouse group is segregated into group “A” and “B”. Statistical significance between groups was assessed using the Kruskal-Wallis test followed by Dunn’s multiple comparison test.
Mentions: To better understand the nature of the inflammation in Muc2-/- mice, we assessed the local cytokine environment and correlated it with the local cellular composition in the same colon segment of the same individual. To achieve this, the proximal, middle and distal colon segments were each divided in half and cytokines were quantified in one half, while cell populations were analyzed by flow cytometry in the remaining half. In general, inflammatory cytokine production increased from the proximal to distal colon (Fig 3A–3E), which was particularly apparent for IL-6. In the distal colon of colitic mice, the concentration of pro-inflammatory cytokines seemed to segregate the mice into subgroups (Fig 3, far right, groups “A” and “B”). That is, group B colitic mice had higher levels of IL-6, IL-1β, TNFα, IFN-γ and IL-17a together with significantly lower IL-10 in the distal colon. These same mice were regarded as colitic in all three sections of the colon except for one mouse (beige symbol), which did not have elevated neutrophils in the proximal colon (Figure A in S1 Fig). In contrast, group A colitic mice had either unchanged or reduced levels of the pro-inflammatory cytokines in the distal colon as well as reduced IL-10 (Fig 3A–3G, far right). Unlike group B mice, group A animals had increased neutrophil influx only in the distal colon (Figure A in S1 Fig and Fig 3). Thus, colitic mice can be divided into A and B subgroups based on cytokine profile in the distal colon and whether increased neutrophils has spread proximally.

Bottom Line: Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria.The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology.These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology and the Mucosal Immunobiology and Vaccine Center (MIVAC), Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
Mucus alterations are a feature of ulcerative colitis (UC) and can drive inflammation by compromising the mucosal barrier to luminal bacteria. The exact pathogenesis of UC remains unclear, but CD4+ T cells reacting to commensal antigens appear to contribute to pathology. Given the unique capacity of dendritic cells (DCs) to activate naive T cells, colon DCs may activate pathogenic T cells and contribute to disease. Using Muc2-/- mice, which lack a functional mucus barrier and develop spontaneous colitis, we show that colitic animals have reduced colon CD103+ CD11b- DCs and increased CD103- CD11b+ phagocytes. Moreover, changes in colonic DC subsets and distinct cytokine patterns distinguish mice with distally localized colitis from mice with colitis spread proximally. Specifically, mice with proximally spread, but not distally contained, colitis have increased IL-1β, IL-6, IL-17, TNFα, and IFNγ combined with decreased IL-10 in the distal colon. These individuals also have increased numbers of CD103+ CD11b+ DCs in the distal colon. CD103+ CD11b+ DCs isolated from colitic but not noncolitic mice induced robust differentiation of Th17 cells but not Th1 cells ex vivo. In contrast, CD103- CD11b+ DCs from colitic Muc2-/- mice induced Th17 as well as Th1 differentiation. Thus, the local environment influences the capacity of intestinal DC subsets to induce T cell proliferation and differentiation, with CD103+ CD11b+ DCs inducing IL-17-producing T cells being a key feature of extensively spread colitis.

No MeSH data available.


Related in: MedlinePlus