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Hematopoietic not systemic impairment of Roquin expression accounts for intestinal inflammation in Roquin-deficient mice.

Montufar-Solis D, Vigneswaran N, Nakra N, Schaefer JS, Klein JR - Sci Rep (2014)

Bottom Line: Lung inflammation consisted of an influx of both T cells and B cells.Small intestinal LPLs had increased numbers of CD44(hi), CD62L(lo), KLRG1(+), ICOS(+) short-lived effector cells, indicating an influx of activated T cells.Following oral infection with L. monocytogenes, Rc3h1(gt/gt) → NL chimeras had more liver pathology and greater numbers of bacteria in the Peyer's patches than NL → NL chimeras.

View Article: PubMed Central - PubMed

Affiliation: Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054 USA.

ABSTRACT
Roquin, an E3 ligase, is involved in curtailing autoimmune pathology as seen from studies using mice with mutated (Rc3h1(san/san)) or disrupted (Rc3h1(gt/gt)) Rc3h1 gene. The extent to which intestinal immunopathology is caused by insufficient Roquin expression in the immune system, or by Roquin impairment in non-hematopoietic cells, has not been determined. Using bone marrow cells from Rc3h1(gt/gt) mice transferred into irradiated normal mice (Rc3h1(gt/gt) → NL chimeras), we show that inflammation developed in the small intestine, kidney, lung, liver, and spleen. Proinflammatory cytokine levels were elevated in lamina propria lymphocytes (LPLs). Inflammation in the liver was accompanied by areas of hepatocyte apoptosis. Lung inflammation consisted of an influx of both T cells and B cells. Small intestinal LPLs had increased numbers of CD44(hi), CD62L(lo), KLRG1(+), ICOS(+) short-lived effector cells, indicating an influx of activated T cells. Following oral infection with L. monocytogenes, Rc3h1(gt/gt) → NL chimeras had more liver pathology and greater numbers of bacteria in the Peyer's patches than NL → NL chimeras. These findings demonstrate that small intestinal inflammation in Rc3h1(san/san) and Rc3h1(gt/gt) mice is due to a failure of Roquin expression in the immune system and not to insufficient systemic Roquin expression.

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Histopathological analysis of intestinal tissue sections from (a) Rc3h1gt/gt mice, (b) Rc3h1gt/gt → NL chimeras, and (c) NL → NL chimeras for the duodenum, jejunum, ileum, and cecum. Note the areas of inflammation (boxed regions) in intestinal tissues of Rc3h1gt/gt and Rc3h1gt/gt → NL chimeras. Micrographs are 100 × original magnification; scale bars are 100 μm. (d) Mean pathology scores ± SEM of 8 Rc3h1gt/gt mice, 5 Rc3h1gt/gt → NL chimeras, and 4 NL → NL chimeras. *p < 0.05, ♦p < 0.01 compared to NL → NL chimeras. (e) Mean numbers of small intestine LPLs ± SEM of 5 Rc3h1gt/gt → NL chimeras and 4 NL → NL chimeras. *p < 0.05 compared to NL → NL chimeras.
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f1: Histopathological analysis of intestinal tissue sections from (a) Rc3h1gt/gt mice, (b) Rc3h1gt/gt → NL chimeras, and (c) NL → NL chimeras for the duodenum, jejunum, ileum, and cecum. Note the areas of inflammation (boxed regions) in intestinal tissues of Rc3h1gt/gt and Rc3h1gt/gt → NL chimeras. Micrographs are 100 × original magnification; scale bars are 100 μm. (d) Mean pathology scores ± SEM of 8 Rc3h1gt/gt mice, 5 Rc3h1gt/gt → NL chimeras, and 4 NL → NL chimeras. *p < 0.05, ♦p < 0.01 compared to NL → NL chimeras. (e) Mean numbers of small intestine LPLs ± SEM of 5 Rc3h1gt/gt → NL chimeras and 4 NL → NL chimeras. *p < 0.05 compared to NL → NL chimeras.

Mentions: Radiation chimeras were generated as described in the Materials and Methods. Mice were studied between 6 and 21 weeks of age. Histopathological analyses of blinded tissue sections were done for the duodenum, jejunum, ileum, cecum, ascending colon, transverse colon, descending colon, liver, kidney, lung, and spleen. The small intestine of Rc3h1gt/gt mice and Rc3h1gt/gt → NL chimeras exhibited variable degrees of inflammation and villus atrophy depending upon the region (Fig. 1, rows a and b, respectively). Inflammation and tissue injury of the organs were unremarkable in control NL → NL chimeras (Fig. 1, row c). The average small intestine pathology scores are shown in Fig. 1d, which indicated that inflammation was present throughout the duodenum, jejunum, and ileum of Rc3h1gt/gt and Rc3h1gt/gt → NL chimeras. Similar to our observation using Rc3h1san/san mice7, Rc3h1gt/gt → NL chimeras were devoid of inflammation in the colon (data not shown). Rc3h1gt/gt → NL chimeras also had significantly more lamina propria lymphocytes (LPLs) than NL → NL mice (Fig. 1e).


Hematopoietic not systemic impairment of Roquin expression accounts for intestinal inflammation in Roquin-deficient mice.

Montufar-Solis D, Vigneswaran N, Nakra N, Schaefer JS, Klein JR - Sci Rep (2014)

Histopathological analysis of intestinal tissue sections from (a) Rc3h1gt/gt mice, (b) Rc3h1gt/gt → NL chimeras, and (c) NL → NL chimeras for the duodenum, jejunum, ileum, and cecum. Note the areas of inflammation (boxed regions) in intestinal tissues of Rc3h1gt/gt and Rc3h1gt/gt → NL chimeras. Micrographs are 100 × original magnification; scale bars are 100 μm. (d) Mean pathology scores ± SEM of 8 Rc3h1gt/gt mice, 5 Rc3h1gt/gt → NL chimeras, and 4 NL → NL chimeras. *p < 0.05, ♦p < 0.01 compared to NL → NL chimeras. (e) Mean numbers of small intestine LPLs ± SEM of 5 Rc3h1gt/gt → NL chimeras and 4 NL → NL chimeras. *p < 0.05 compared to NL → NL chimeras.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4017215&req=5

f1: Histopathological analysis of intestinal tissue sections from (a) Rc3h1gt/gt mice, (b) Rc3h1gt/gt → NL chimeras, and (c) NL → NL chimeras for the duodenum, jejunum, ileum, and cecum. Note the areas of inflammation (boxed regions) in intestinal tissues of Rc3h1gt/gt and Rc3h1gt/gt → NL chimeras. Micrographs are 100 × original magnification; scale bars are 100 μm. (d) Mean pathology scores ± SEM of 8 Rc3h1gt/gt mice, 5 Rc3h1gt/gt → NL chimeras, and 4 NL → NL chimeras. *p < 0.05, ♦p < 0.01 compared to NL → NL chimeras. (e) Mean numbers of small intestine LPLs ± SEM of 5 Rc3h1gt/gt → NL chimeras and 4 NL → NL chimeras. *p < 0.05 compared to NL → NL chimeras.
Mentions: Radiation chimeras were generated as described in the Materials and Methods. Mice were studied between 6 and 21 weeks of age. Histopathological analyses of blinded tissue sections were done for the duodenum, jejunum, ileum, cecum, ascending colon, transverse colon, descending colon, liver, kidney, lung, and spleen. The small intestine of Rc3h1gt/gt mice and Rc3h1gt/gt → NL chimeras exhibited variable degrees of inflammation and villus atrophy depending upon the region (Fig. 1, rows a and b, respectively). Inflammation and tissue injury of the organs were unremarkable in control NL → NL chimeras (Fig. 1, row c). The average small intestine pathology scores are shown in Fig. 1d, which indicated that inflammation was present throughout the duodenum, jejunum, and ileum of Rc3h1gt/gt and Rc3h1gt/gt → NL chimeras. Similar to our observation using Rc3h1san/san mice7, Rc3h1gt/gt → NL chimeras were devoid of inflammation in the colon (data not shown). Rc3h1gt/gt → NL chimeras also had significantly more lamina propria lymphocytes (LPLs) than NL → NL mice (Fig. 1e).

Bottom Line: Lung inflammation consisted of an influx of both T cells and B cells.Small intestinal LPLs had increased numbers of CD44(hi), CD62L(lo), KLRG1(+), ICOS(+) short-lived effector cells, indicating an influx of activated T cells.Following oral infection with L. monocytogenes, Rc3h1(gt/gt) → NL chimeras had more liver pathology and greater numbers of bacteria in the Peyer's patches than NL → NL chimeras.

View Article: PubMed Central - PubMed

Affiliation: Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054 USA.

ABSTRACT
Roquin, an E3 ligase, is involved in curtailing autoimmune pathology as seen from studies using mice with mutated (Rc3h1(san/san)) or disrupted (Rc3h1(gt/gt)) Rc3h1 gene. The extent to which intestinal immunopathology is caused by insufficient Roquin expression in the immune system, or by Roquin impairment in non-hematopoietic cells, has not been determined. Using bone marrow cells from Rc3h1(gt/gt) mice transferred into irradiated normal mice (Rc3h1(gt/gt) → NL chimeras), we show that inflammation developed in the small intestine, kidney, lung, liver, and spleen. Proinflammatory cytokine levels were elevated in lamina propria lymphocytes (LPLs). Inflammation in the liver was accompanied by areas of hepatocyte apoptosis. Lung inflammation consisted of an influx of both T cells and B cells. Small intestinal LPLs had increased numbers of CD44(hi), CD62L(lo), KLRG1(+), ICOS(+) short-lived effector cells, indicating an influx of activated T cells. Following oral infection with L. monocytogenes, Rc3h1(gt/gt) → NL chimeras had more liver pathology and greater numbers of bacteria in the Peyer's patches than NL → NL chimeras. These findings demonstrate that small intestinal inflammation in Rc3h1(san/san) and Rc3h1(gt/gt) mice is due to a failure of Roquin expression in the immune system and not to insufficient systemic Roquin expression.

Show MeSH
Related in: MedlinePlus