Abstract
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 pro-inflammatory bioactive lipid and that dysregulation of ACER3 and C18:1-ceramide may contribute to the pathogenesis of inflammatory diseases including cancer.
Highlights
Received 22.10.15; revised 13.1.16; accepted 19.1.16; Edited by H-U Simon acid synergistically increase C16-ceramide in primary mouse peritoneal macrophages (PMs) by activating de novo biosynthesis of ceramides and that inhibiting the C16-ceramide increase attenuates LPS-induced production of TNF-α and IL-1β in PMs
Having demonstrated that Acer[3] downregulation mediates LPS-induced elevation of C18:1-ceramide, we investigated if loss of Acer[3] affected the expression of proinflammatory cytokines in blood mononuclear cells (BMCs), PMs and colonic epithelial cells (CECs) stimulated by LPS
Acer[3] deficiency did not affect the basal mRNA levels of these pro-inflammatory cytokines (Supplementary Figures S3A, S3B, and S3C). These results suggest that Acer[3] deficiency potentiates LPS-induced upregulation of pro-inflammatory cytokines in immune cells and CECs
Summary
Received 22.10.15; revised 13.1.16; accepted 19.1.16; Edited by H-U Simon acid synergistically increase C16-ceramide in primary mouse peritoneal macrophages (PMs) by activating de novo biosynthesis of ceramides and that inhibiting the C16-ceramide increase attenuates LPS-induced production of TNF-α and IL-1β in PMs. Fischbeck et al.[8] showed that increasing ceramides in the gut by supplying mice with dietary sphingomyelins, a precursor of ceramides, aggravates mouse colitis. These results suggest that increased levels of ceramides may contribute to the pathogenesis of IBD. We found that Acer[3] deficiency aggravates dextran sulfate sodium (DSS)-induced colitis and colitis-associated colorectal cancer (CAC) in a murine model. These findings indicate that Acer3/ACER3 and C18:1-ceramide are novel modulators in the innate immune response and that their dysregulation may contribute to the pathogenesis of inflammatory diseases
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