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Structural and signaling functions of sphingomyelinases during inflammation
Sphingolipids are lipid molecules with structural, signaling, and metabolic functions. Sphingomyelinases (SMases) convert sphingomyelin, a mostly structural lipid, to ceramide, a bioactive metabolite. Two of the five known SMases play distinct roles in inflammation. Neutral sphingomyelinase-2 (nSMase-2) is a plasma membrane-localized enzyme and mediates the hepatocyte response to IL-1b. Our experiments have identified PP2A, IRAK1, JNK, FoxO1, and the insulin-like growth factor binding protein 1 (IGFBP1) as components of a novel pathway in the IL-1b signaling network that are dependent upon nSMase-2. Surprisingly, we also found that conditions associated with chronic, subclinical inflammation (like oxidative stress, hepatic steatosis, and aging), affect the basal activity of nSMase2, causing up-regulation of that specific pathway and IL-1b hyperresponse. Experiments in mice and rats also show that silencing of nSMase-2 in hepatocytes can be achieved in vivo and can help alleviate an exacerbated IL-1b response.
Acid sphingomyelinase (ASMase) is localized in the endo-lysosomal compartment of the cells and impacts the dynamics of lipid raft domains and endosomes. These effects are especially important for the functions of macrophages during the innate immune response. In activated macrophages, ASMase activity modulates the magnitude of LPS-induced secretion of TNFa. The mechanism is complex and involves the regulation of: (a) the activity of TACE, an enzyme that cleaves the inactive TNFa precursor (pro-TNFa) to its active form and (b) the rate of recycling of pro-TNFa between lysosomes and the plasma membrane. Together, these experiments delineate a novel understanding of the bioactive functions of SMases in chronic and acute inflammation.
Keywords: Inflammation, liver, macrophage