title: TLR4 activation under lipotoxic conditions leads to synergistic macrophage cell death through a TRIF-dependent pathway.
abstract: Macrophage dysfunction in obesity and diabetes may predispose to the development of diabetic complications, such as infection and impaired healing after tissue damage. Saturated fatty acids, such as palmitate, are present at elevated concentrations in the plasma of patients with metabolic disease and may contribute to the pathogenesis of diabetes and its sequelae. To examine the effect of lipid excess on macrophage inflammatory function, we determined the influence of palmitate on LPS-mediated responses in peritoneal macrophages. Palmitate and LPS led to a profound synergistic cell death response in both primary and RAW 264.7 macrophages. The cell death had features of apoptosis and necrosis and was not dependent on endoplasmic reticulum stress, ceramide generation, or reactive oxygen species production. Instead, we uncovered a macrophage death pathway that required TLR4 signaling via TRIF but was independent of NF-κB, MAPKs, and IRF3. A significant decrease in macrophage lysosomal content was observed early in the death pathway, with evidence of lysosomal membrane damage occurring later in the death response. Overexpression of the transcription factor TFEB, which induces a lysosomal biogenic program, rescued the lysosomal phenotype and improved viability in palmitate- and LPS-treated cells. Our findings provide new evidence for cross-talk between lipid metabolism and the innate immune response that converges on the lysosome.
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Schilling
authors.forename: Heather M
authors.initials: HM
authors.lastname: Machkovech
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Abhinav
authors.initials: A
authors.lastname: Diwan
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002461:Cell Line, Transformed / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048909:Diabetes Complications / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007425:Intracellular Membranes / Q000473:pathology; D050356:Lipid Metabolism / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008247:Lysosomes / Q000276:immunology* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010168:Palmitates / Q000633:toxicity*; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014162:Transfection
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D008070:Lipopolysaccharides; D010168:Palmitates; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C484068:Tcfeb protein, mouse; C493487:Tlr4 protein, mouse