Macrophage alternative activation confers protection against lipotoxicity-induced cell death

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Macrophage alternative activation confers protection against lipotoxicity-induced cell death

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Title: Macrophage alternative activation confers protection against lipotoxicity-induced cell death
Author: Dai, Lingling; Bhargava, Prerna; Stanya, Kristopher J.; Alexander, Ryan K.; Liou, Yae-Huei; Jacobi, David; Knudsen, Nelson H.; Hyde, Alexander; Gangl, Matthew R.; Liu, Sihao; Lee, Chih-Hao

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Citation: Dai, L., P. Bhargava, K. J. Stanya, R. K. Alexander, Y. Liou, D. Jacobi, N. H. Knudsen, et al. 2017. “Macrophage alternative activation confers protection against lipotoxicity-induced cell death.” Molecular Metabolism 6 (10): 1186-1197. doi:10.1016/j.molmet.2017.08.001.
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Abstract: Objective: Alternative activation (M2) of adipose tissue resident macrophage (ATM) inhibits obesity-induced metabolic inflammation. The underlying mechanisms remain unclear. Recent studies have shown that dysregulated lipid homeostasis caused by increased lipolysis in white adipose tissue (WAT) in the obese state is a trigger of inflammatory responses. We investigated the role of M2 macrophages in lipotoxicity-induced inflammation. Methods: We used microarray experiments to profile macrophage gene expression regulated by two M2 inducers, interleukin-4 (Il-4), and peroxisome proliferator-activated receptor delta/gamma (Pparδ/Pparγ) agonists. Functional validation studies were performed in bone marrow-derived macrophages and mice deprived of the signal transducer and activator of transcription 6 gene (Stat6; downstream effector of Il-4) or Pparδ/Pparγ genes (downstream effectors of Stat6). Palmitic acid (PA) and β-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. Results: Profiling of genes regulated by Il-4 or Pparδ/Pparγ agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Pparδ/Pparγ increases the susceptibility of macrophages to PA-induced cell death. NLR family pyrin domain containing 3 (Nlrp3) inflammasome activation by PA in the presence of lipopolysaccharide is also increased in Stat6−/− macrophages and to a lesser extent, in Pparδ/γ−/− macrophages. In concert, β-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Pparδ/γ−/− or Stat6−/− mice. Conclusions: Our data suggest that ATM cell death is closely linked to metabolic inflammation. Within WAT where concentrations of free fatty acids fluctuate, M2 polarization regulated by the Stat6-Ppar axis enhances ATM's tolerance to lipid-mediated stress, thereby maintaining the homeostatic state.
Published Version: doi:10.1016/j.molmet.2017.08.001
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