Ceramide signaling in immunity: a molecular perspective

Abstract

Ceramides are bioactive lipids that play a crucial role in cellular signaling and structural integrity (Nat Rev Mol Cell Biol 19:175-191, 2018). As members of the sphingolipid family, ceramides consist of a sphingoid base attached to a fatty acid (Annu Rev Biophys 47:633-654, 2018). Their unique structure confers both hydrophobic and amphipathic properties, enabling them to organize into membrane microdomains that influence cellular dynamics (Annu Rev Biophys 47:633-654, 2018). In recent years, ceramides have garnered attention for their role in modulating a range of cellular and organismal functions. Unlike other lipids that primarily serve structural roles, ceramides act as bioactive lipids in key signaling pathways, mediating stress responses such as inflammation, oxidative stress, growth inhibition, metabolism, autophagy, and apoptosis (J Lipid Res 60:913-918, 2019). Their regulatory effects are particularly important in immune cells, where ceramides can influence cell fate, modulate cellular metabolism, affect cytokine production, and dictate responses to external stimuli (Nature 510:58-67, 2014). Since ceramides maintain a dynamic equilibrium with other sphingolipids within a cell, understanding their role in immune cells in isolation provides only a partial perspective. Nevertheless, as a bioactive lipid and the central precursor of other sphingolipids, ceramides play a pivotal role in immune cells, deserving focused attention.

Keywords: Ceramides; Dyslipidemia; Immune cells; Inflammation; Signaling; Sphingolipids.

Fig. 1

Sphingolipid metabolic pathways, organelles, and key sphingolipid structures. Schematic depicting the key pathways and enzymes involved in ceramide biosynthesis and degradation. Abbreviations: aSMase, acid sphingomyelinase; CDase, ceramidase; aCDase, acid ceramidase; CERS, ceramide synthase; CERT, ceramide transporter; Co-A, coenzyme A; DES, dihydroceramide desaturase; GCS, glucosylceramide synthase; GCase, glucosylceramidase; KDSR, 3-ketodihydrosphingosine reductase; SPTLC, serine palmitoyltransferase; SMS, sphingomyelin synthase; SPHK, sphingosine kinase; SMase, sphingomyelinase; S1PP, sphingosine 1-phosphate phosphatase

Fig. 2

Ceramide signaling in innate immune cells. Summary of the pathways involved in promoting ceramide biosynthesis and its molecular and functional effects in innate immune cell subsets (macrophages, dendritic cells, neutrophils) and NK cells. Abbreviations: FABP, Fatty Acid- Binding Protein; IL-10, Interleukin 10; IL-10R, Interleukin receptor 10; KLA, Kdo2-lipid A; LPS, Lipopolysaccharide; MAPK, Mitogen-activated protein kinase; NETosis, Neutrophil Extracellular Trap formation; NF-kB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-like receptor family pyrin domain-containing 3; PKC, Protein Kinase C; PI3K, Phosphoinositide 3-kinase; ROS, Reactive oxygen species; SFA, Saturated fatty acid; TLR4, Toll-like receptor 4; TNF, Tumor Necrosis Factor; TNFR, Tumor Necrosis Factor Receptor; TNF-α, Tumor necrosis factor-alpha

Fig. 3

Ceramide signaling in adaptive immune cells. Overview of the pathways involved in inducing ceramide biosynthesis and its molecular and functional impacts on adaptive immune cell subsets (B cells, CD8 and CD4-Tcells). Abbreviations: BCR, B cell receptor; CRAC: Calcium Release-Activated Calcium channels; GlcCer, Glucosylceramide; NF-kB, Nuclear Factor kappa-light-chain-enhancer of activated B cells; NFAT, Nuclear Factor of Activated T cells; SMase, sphingomyelinase; TCR, T cell receptor