Sphingomyelin 14:0 – the link between obesity and neuroinflammation

Abstract

AbstractBackgroundOur laboratory has demonstrated that the consumption of a Western‐type diet (WD), triggers sterile inflammation and long‐term epigenetic reprogramming of myeloid cells, altering their immune response (Christ et al 2018). However, the precise molecular trigger mediating these changes was unknown. We have recently identified that during these WD conditions, there is an increase in circulating sphingomyelin 14:0 (S14), which was associated with atherosclerotic disease progression. As obesity, WD and atherosclerosis are all risk factors for Alzheimer’s disease (AD) and dementia, we set out to determine whether S14 was the signaling factor linking these conditions with AD development.MethodSerum samples were obtained from obese patients for lipidomic analysis. Mice were fed a high‐fat diet mimicking WD for a period of 8 weeks, before samples were obtained for lipidomic analysis. Microglia and macrophages were prepared from wildtype, TLR4−/−, Trif−/− and MyD88−/− mice to assess whether myeloid cells recognize S14, and the molecular pathways triggered by the lipid. Cells were prepared for RNA sequencing, to determine the genes and networks induced by S14. These genes and pathways were confirmed at a protein level by western blot and flow cytometry, and at a functional level using real‐time metabolic, and phagocytic assays. Results were confirmed in human myeloid cells.ResultLipidomic analysis confirmed that obese patients have increased circulating levels of S14, which were associated with inflammatory markers and cardiovascular disease. In vitro, we found using RNAseq that S14 triggers an extensive increase in pro‐inflammatory genes and pathways. We confirmed that S14 binds to TLR4/MD2 triggering NFkB activation and the release of TNFα in macrophages and microglial cells. S14 also reduced metabolic function and altered phagocytic capacity in microglia.ConclusionWe have found that S14, a lipid increased during obesity and WD conditions, is a novel TLR4 ligand that can activate macrophages and microglia triggering sterile inflammation. This pathway is conserved between murine and human cells. Critically, S14 reduced microglial phagocytosis, and rewired cellular metabolism. Together, our data shows for the first time that S14 is an immune stimulus, capable of triggering the innate immune responses and inflammation associated with dementia progression.