Abstract
Dysregulation of immune responses in the gut often associates with inflammatory bowel diseases (IBD). Mouse CD1d1, an ortholog of human CD1d mainly participating in lipid-antigen presentation to NKT cells, is able to generate intrinsic signals upon stimulation. Mice with macrophage-specific CD1d1 deficiency (LymCD1d1-/- ) acquire resistance to dextran sodium sulfate (DSS)-induced colitis, attributing to the transcriptional inhibition of NLRP3 inflammasome components. The hyperactivation of NLRP3 inflammasome accounts for gut epithelial proliferation and intestine-blood barrier integrity. Mechanistically, occupancy by the natural ligand glycosphingolipid iGb3, CD1d1 responds with intracellular Ser330 dephosphorylation thus to reduce the Peroxiredoxin 1 (PRDX1)-associated AKT-STAT1 phosphorylation and subsequent NF-κB activation, eventually causing transcriptional down-regulation of Nlrp3 and its immediate substrates Il1b and Il18 in macrophages. Therefore, the counterbalancing role of CD1d1 in macrophages appears to determine severity of DSS-mediated colitis in mice. These findings propose new intervention strategies for treating IBD and other inflammatory disorders.