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Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 (Cdcs1) locus.

ABSTRACT: Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet(-/-).Rag2(-/-) double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of colorectal cancer. However, we observed that colitis in T-bet(-/-).Rag2(-/-) mice on a C57BL/6 background was significantly less severe. Quantitative trait locus analysis using an N2 backcross strategy revealed a single major quantitative trait locus on chromosome 3 that mapped to the Cdcs1 (cytokine deficiency-induced colitis susceptibility-1) locus previously identified in the Il10(-/-) and Gnai2(-/-) colitis models. Congenic introduction of the susceptible Cdcs1 interval from C3H/He into the C57BL/6 background restored colitis severity. Bone marrow reconstitution experiments further mapped the effect of host genetics on disease severity to the hematopoietic compartment. There were distinct differences in the expression of several Cdcs1 genes in bone marrow-derived dendritic cells from Cdcs1 congenic mice. We conclude that the Cdcs1 locus controls colitis severity in T-bet(-/-).Rag2(-/-) mice through innate immune cells.

SUBMITTER: Ermann J

PROVIDER: S-EPMC3084042 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 (Cdcs1) locus.

Ermann Joerg J Garrett Wendy S WS Kuchroo Juhi J Rourida Khadija K Glickman Jonathan N JN Bleich Andre A Glimcher Laurie H LH

Proceedings of the National Academy of Sciences of the United States of America 20110411 17

Genetic modifier loci influence the phenotypic expression of many Mendelian traits; insight into disease pathogenesis gained from their identification in animal disease models may impact the treatment of human multigenic disorders. We previously described an innate immune-driven model of spontaneous ulcerative colitis in T-bet(-/-).Rag2(-/-) double-deficient mice that resembles human ulcerative colitis. On a BALB/c background, this disease is highly penetrant and results in the development of co ...[more]

PMID: 21482794

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Project description:Increasing studies suggest that ceramides differing in acyl chain length and/or degree of unsaturation have distinct roles in mediating biological responses. However, still much remains unclear about regulation and role of distinct ceramide species in the immune response. Here, we demonstrate that alkaline ceramidase 3 (Acer3) mediates the immune response by regulating the levels of C18:1-ceramide in cells of the innate immune system and that Acer3 deficiency aggravates colitis in a murine model by augmenting the expression of pro-inflammatory cytokines in myeloid and colonic epithelial cells (CECs). According to the NCBI Gene Expression Omnibus (GEO) database, ACER3 is downregulated in immune cells in response to lipopolysaccharides (LPS), a potent inducer of the innate immune response. Consistent with these data, we demonstrated that LPS downregulated both Acer3 mRNA levels and its enzymatic activity while elevating C(18:1)-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C(18:1)-ceramide and the expression of pro-inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C(18:1)-ceramide, but not C18:0-ceramide, potentiated LPS-induced expression of pro-inflammatory cytokines in immune cells. In the mouse model of dextran sulfate sodium-induced colitis, Acer3 deficiency augmented colitis-associated elevation of colonic C(18:1)-ceramide and pro-inflammatory cytokines. Acer3 deficiency aggravated diarrhea, rectal bleeding, weight loss and mortality. Pathological analyses revealed that Acer3 deficiency augmented colonic shortening, immune cell infiltration, colonic epithelial damage and systemic inflammation. Acer3 deficiency also aggravated colonic dysplasia in a mouse model of colitis-associated colorectal cancer. Taken together, these results suggest that Acer3 has an important anti-inflammatory role by suppressing cellular or tissue C(18:1)-ceramide, a potent pro-inflammatory bioactive lipid and that dysregulation of ACER3 and C(18:1)-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer.

Dataset Information

Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 (Cdcs1) locus.

Publications

Severity of innate immune-mediated colitis is controlled by the cytokine deficiency-induced colitis susceptibility-1 (Cdcs1) locus.

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