Sphingolipid metabolism during Toll‐like receptor 4 (TLR4)‐mediated macrophage activation

Abstract

Macrophage activation in response to stimulation of Toll‐like receptor 4 (TLR4) provides a paradigm for investigating energy metabolism that regulates the inflammatory response. TLR4‐mediated pro‐inflammatory macrophage activation is characterized by increased glycolysis and altered mitochondrial metabolism, supported by selective amino acid uptake and/or usage. Fatty acid metabolism remains as a highly complex rewiring that accompanies classical macrophage activation. TLR4 activation leads to de novo synthesis of fatty acids, which flux into sphingolipids, complex lipids that form the building blocks of eukaryotic cell membranes and regulate cell function. Here, we review the importance of TLR4‐mediated de novo synthesis of membrane sphingolipids in macrophages. We first highlight fatty acid metabolism during TLR4‐driven macrophage immunometabolism. We then focus on the temporal dynamics of sphingolipid biosynthesis and emphasize the modulatory role of some sphingolipid species (i.e. sphingomyelins, ceramides and glycosphingolipids) on the pro‐inflammatory and pro‐resolution phases of LPS/TLR4 activation in macrophages.

Immunolipidomics Reveals a Globoside Network During the Resolution of Pro-Inflammatory Response in Human Macrophages

“…For instance, all sphingoid base species (SPB, the precursor of ceramides), peak during the proinflammatory phase (3h), while their products (ceramides and their derivatives -HexCer and globosides) accumulate during the resolution phase. The early production of SPB upon TLR4 activation is in line with previous reports (25) and the late production of ceramide-derived sphingolipids is due to their relative structural complexity that requires additional enzymatic steps (29). Our results also show temporal differences in the production of sphingolipid subclasses, suggesting that the fatty acid chain length of each lipid specie affects their kinetics following LPS treatment.…”

“…Following partial correlation analysis (to identify relevant associations), 34 lipids, 19 lipid pathway-related transcripts and 2328 genome-wide transcripts were retained ( Figure 5A , see Methods ). Among the resolution lipids, globosides and CE showed the highest inter-individual variability ( Figures 2A, B ), suggesting their potential regulatory effects on LPS/TLR4 in macrophages ( 29 ). We thus focused on these lipid species and hypothesized that specific gene networks could be associated with their production in human macrophages.…”

“…immunolipidomics) occur at the level of individual lipids and/or as part of lipid droplets ( 8 , 12 , 13 , 16 , 20 ). A less studied but equally important aspect, is the usage of specific lipids such as sphingolipids by the macrophage to regulate the ongoing TLR4 trafficking and signalling events and the evolution of intracellular pathways that shift from pro-inflammatory (3h-8h) to resolution (8h-24h) phases ( 29 , 30 ). Hence reprogramming of lipid metabolism coordinate regulatory and effector pathways in LPS-stimulated macrophages.…”

“…Indeed, while most lipid classes follow indistinctive kinetics, sphingolipid classes show clear patterns during pro-inflammatory and resolution phases following the LPS response. This could be explained by the LPS-induced de novo biosynthesis of fatty acids, which produce palmitate as a building block of sphingolipids in macrophages ( 29 ). It is therefore not surprising that the LPS-induced de novo synthesis of sphingolipids follows well-defined kinetics in human macrophages.…”

The Role of TLR2 in Infectious Diseases Caused by Mycobacteria: From Cell Biology to Therapeutic Target

“…Considering the broad function of TLR2 in many diseases ( Figure 4 ), a further understanding of its function is of great importance. It is likely that TLR signaling integrates control of innate immune responses and metabolism, as suggested by various studies on rodents and zebrafish [ 109 , 208 , 209 ]. Therefore, theoretical modelling that integrates transcriptional and metabolic responses, for example, applied by van Steijn et al, will be useful to understand the effects of therapeutics that target TLR signaling [ 210 ].…”