Emerging roles of the acid sphingomyelinase/ceramide pathway in metabolic and cardiovascular diseases: Mechanistic insights and therapeutic implications

Figure 2 The acid sphingomyelinase/ceramide pathway induces chronic inflammation in macrophages. Activation of acid sphingomyelinase by bacterial product lipopolysaccharides, cell damage signalling and endoplasmic reticulum signalling causes increased ceramide. Pathogens attach to the extracellular segment of the Toll-like receptor on macrophages due to altered cell membrane composition and permeability caused by excess ceramide. This attracts bridging proteins like MyD88, activates the nuclear factor-κB and mitogen-activated protein kinase pathways, and activates the NOD-like receptor protein 3 inflammasome, which in turn activates caspase-1 and releases inflammatory cytokines (tumor necrosis factor-alpha and interleukins). Caspases 1 are activated and inflammatory cytokines (tumor necrosis factor-alpha and interleukins) are released when the NOD-like receptor protein 3 inflammasome is activated. PAMPs: Pathogen-associated molecular patterns; LPS: Lipopolysaccharides; TLR: Toll-like receptor; IRAK: Interleukin-1R associated kinase; TRAF6: Tumor necrosis factor receptor associated factor 6; Cer: Ceramide; ROS: Reactive oxygen species; ASMase: Acid sphingomyelinase; ER: Endoplasmic reticulum; NOX: NADPH oxidase; TAK1: Transforming growth factor β-activated kinase 1; TAB1: Transforming growth factor β-activated kinase 1 binding protein 1; TAB2: Transforming growth factor β-activated kinase 1 binding protein 2; MAPK: Mitogen-activated protein kinase; SM: Sphingomyelin; NF-κB: Nuclear factor-κB; NLRP3: NLR family pyrin domain containing 3; TNF-α: Tumor necrosis factor-alpha; ILs: Interleukins.