Macrophage alternative activation confers protection against lipotoxicity-induced cell death

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 (Ppar delta/Ppar gamma) 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 Ppar delta/Ppar gamma genes (downstream effectors of Stat6). Palmitic acid (PA) and beta-adrenergic agonist were employed to induce macrophage lipid loading in vitro and in vivo, respectively. Results: Profiling of genes regulated by Il-4 or Ppar delta/Ppar gamma agonists reveals that alternative activation promotes the cell survival program, while inhibiting that of inflammation-related cell death. Deletion of Stat6 or Ppar delta/Ppar gamma 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 Ppar delta/gamma(-/-) macrophages. In concert, beta-adrenergic agonist-induced lipolysis results in higher levels of cell death and inflammatory markers in ATMs derived from myeloid-specific Ppar delta/gamma(-/-) 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. (C) 2017 The Authors. Published by Elsevier GmbH.