TY - JOUR
T1 - Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system
AU - Wang, K.
AU - Xu, R.
AU - Snider, A. J.
AU - Schrandt, J.
AU - Li, Y.
AU - Bialkowska, A. B.
AU - Li, M.
AU - Zhou, J.
AU - Hannun, Y. A.
AU - Obeid, L. M.
AU - Yang, V. W.
AU - Mao, C.
N1 - Funding Information:
We would like to acknowledge the technical support provided by the Research Histology Core Laboratory, Department of Pathology, Stony Brook University. We thank Izolda Mileva in the Lipidomics Core Facility at Stony Brook University for performing sphingolipidomic analyses. We thank Masayuki Wada, Nicolas Coant and Mónica García-Barros at Department of Medicine, Stony Brook University for their advices on establishing and examining DSS-colitis and AOM/DSS models. This work was supported, in whole or in part, by National Institutes of Health Grants R01CA104834 and R01CA163825 to CM, P01CA097132 to YAH and CM, and R01CA084197 and R01CA172113 to VWY.
Funding Information:
Acknowledgements. We would like to acknowledge the technical support provided by the Research Histology Core Laboratory, Department of Pathology, Stony Brook University. We thank Izolda Mileva in the Lipidomics Core Facility at Stony Brook University for performing sphingolipidomic analyses. We thank Masayuki Wada, Nicolas Coant and Mónica García-Barros at Department of Medicine, Stony Brook University for their advices on establishing and examining DSS-colitis and AOM/DSS models. This work was supported, in whole or in part, by National Institutes of Health Grants R01CA104834 and R01CA163825 to CM, P01CA097132 to YAH and CM, and R01CA084197 and R01CA172113 to VWY.
Publisher Copyright:
© 2016 Macmillan Publishers Limited.
PY - 2016
Y1 - 2016
N2 - 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 C18:1-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C18:1-ceramide and the expression of pro-inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C18:1-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 C18:1-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 C18:1-ceramide, a potent proinflammatory bioactive lipid and that dysregulation of ACER3 and C18:1-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer.
AB - 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 C18:1-ceramide, a substrate of Acer3, in murine immune cells or CECs. Knocking out Acer3 enhanced the elevation of C18:1-ceramide and the expression of pro-inflammatory cytokines in immune cells and CECs in response to LPS challenge. Similar to Acer3 knockout, treatment with C18:1-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 C18:1-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 C18:1-ceramide, a potent proinflammatory bioactive lipid and that dysregulation of ACER3 and C18:1-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer.
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U2 - 10.1038/cddis.2016.36
DO - 10.1038/cddis.2016.36
M3 - Article
C2 - 26938296
AN - SCOPUS:85011074721
SN - 2041-4889
VL - 7
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 3
M1 - e2124
ER -