TLR4 activation under lipotoxic conditions leads to synergistic macrophage cell
death through a TRIF-dependent pathway.
Authors Schilling JD, Machkovech HM, He L, Diwan A, Schaffer JE
Submitted By Jean Schaffer on 3/17/2014
Status Published
Journal Journal of immunology (Baltimore, Md. : 1950)
Year 2013
Date Published 2/1/2013
Volume : Pages 190 : 1285 - 1296
PubMed Reference 23275600
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-?B, 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.

Investigators with authorship
Jean SchafferWashington University in St Louis