T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model

Abstract

To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.

Wumei Pill Ameliorates AOM/DSS-Induced Colitis-Associated Colon Cancer through Inhibition of Inflammation and Oxidative Stress by Regulating S-Adenosylhomocysteine Hydrolase- (AHCY-) Mediated Hedgehog Signaling in Mice

“…Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorder of the intestine and can result in a well-recognized increased risk of colon carcinogenesis [ 13 , 14 ], especially for the development and progression of colitis-associated colorectal cancer (CAC) [ 15 ]. Upon the initiation of CAC, a large number of inflammatory cells, such as macrophage, natural killer cells, and dendritic cells, infiltrate around the colonic tissues [ 16 , 17 ], leading to the increased production of proinflammatory cytokines, which makes colonic tissues in an inflammatory microenvironment. Without effective treatment, persistent inflammatory stimulation will further aggravate CAC [ 18 ].…”

Sphingolipid metabolism in T cell responses after allogeneic hematopoietic cell transplantation

“…However, C14/C16ceramides generated by CerS6 in the mitochondria lead to mitophagy dysfunction in activated T cells, inducing agingdependent metabolic disorders that decreased T-cell central memory phenotype and reduced antitumor immunity in aged mice (36). Germline loss of CerS5 or CerS6 exacerbates inflammation in a dextran sulfate sodium (DSS)-induced colitis mouse model (37,38). These findings demonstrate that CerS isoenzymes play different roles in modulating T-cell biological functions.…”

“…CD4 + Jurkat cells enhance the transcription of all the CerSs except for CerS4 when stimulated with anti-CD3 antibody and IL-2, while silencing CerS5 by shRNA prohibits the upregulation of CerS1, CerS3 and CerS6 and significantly decreases CerS4 transcription upon stimulation (38). CerS5 deficiency in human CD4 + Jurkat cells impairs NF-kB dependent T-cell signal and proper T-cell activation (38). After HCT, pharmacological inhibition of CerS6 with ST1072 reduces the numbers of IFN-g-producing and total human T cells in secondary lymphoid and GVHD target organs in a xeno-GVHD model (41).…”

“…Only scarce reports can be found in studying the role of CerS in human T cells. CD4 + Jurkat cells enhance the transcription of all the CerSs except for CerS4 when stimulated with anti-CD3 antibody and IL-2, while silencing CerS5 by shRNA prohibits the upregulation of CerS1, CerS3 and CerS6 and significantly decreases CerS4 transcription upon stimulation (38). CerS5 deficiency in human CD4 + Jurkat cells impairs NF-kB dependent T-cell signal and proper T-cell activation (38).…”

How sphingolipids affect T cells in the resolution of inflammation

“…In CerS5 knockout mice the number of CD3 + /CD8 + and Treg cells was reduced in the intra-epithelial lymphocyte fraction of the colon and TCR signalling was impaired ( Table 1 ) ( El-Hindi et al, 2020 ). Instead, depletion of CerS4 in T cells led to a constitutively and prolonged TCR activation ( Table1 ) ( El-Hindi et al, 2022 ). These data indicate that the molecular composition of the membrane around the TCR is important for proper T cell activation and can be influenced by sphingolipids of various chain length.…”