Elsevier

Molecular Metabolism

Volume 6, Issue 10, October 2017, Pages 1186-1197
Molecular Metabolism

Original Article
Macrophage alternative activation confers protection against lipotoxicity-induced cell death

https://doi.org/10.1016/j.molmet.2017.08.001Get rights and content
Under a Creative Commons license
open access

Highlights

  • Cell survival is transcriptionally regulated by macrophage alternative activation.

  • Fatty acid-triggered cell death is increased in Pparδ/γ−/− or Stat6−/− macrophages.

  • Il-4-Stat6 signaling suppresses lipotoxicity-induced inflammasome activation.

  • The Stat6-Pparδ/γ axis protects ATMs against lipolysis-induced cell death in vivo.

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.

Keywords

Obesity
Adipose tissue macrophage
Alternative activation
Lipotoxicity
Meta-inflammation

Abbreviations

M2
alternative activation of macrophage
M1
classic activation of macrophage
WAT
white adipose tissue
ATM
adipose tissue resident macrophage
Ppar
peroxisome proliferator-activated receptor
Stat6
signal transducer and activator of transcription 6
PA
palmitic acid
Nlrp3
NLR family pyrin domain containing 3
BMDM
bone marrow derived macrophage
ILC2
type 2 innate lymphoid cell
SVF
stromal vascular fraction
OCR
oxygen consumption rate
Angptl4
angiopoietin-like 4
Sgms1
sphingomyelin synthase 1
Plin2
perilipin 2
Acadvl
acyl-CoA dehydrogenase, very long chain
Slc25a20
solute carrier family 25 member 20
Mogat1
monoacylglycerol O-acyltransferase 1
Mgl1
macrophage galactose-type lectin-1
Arg1
arginase 1
Bcl2
B-cell lymphoma 2
H2-Eb1
histocompatibility 2, class II antigen E beta

Cited by (0)

3

Current address: Institute for Medical Engineering & Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

4

Current address: l'institut du thorax, INSERM, CNRS, UNIV Nantes & CHU Nantes, Nantes, France.

5

Current address: Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037, USA.