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Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
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FABP4/aP2 Regulates Macrophage Redox Signaling and Inflammasome Activation via Control of UCP2

Kaylee A Steen1, Hongliang Xu1, David A Bernlohr2

  • 1Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA.

Molecular and Cellular Biology
|November 1, 2016
PubMed

Insights

Obesity causes inflammation via macrophages. Removing adipocyte fatty acid-binding protein (FABP4/aP2) reduces oxidative stress and inflammasome activation, uncoupling obesity from inflammation.

Area of Science:

  • Metabolic disease research
  • Inflammation and immunology
  • Redox biology

Background:

  • Obesity-linked metabolic disease involves proinflammatory macrophages in adipose tissue, increasing reactive oxygen species (ROS) and chronic inflammation.
  • Adipocyte fatty acid-binding protein (FABP4/aP2) deletion has been shown to decouple obesity from inflammation by upregulating uncoupling protein 2 (UCP2).

Purpose of the Study:

  • To investigate the role of FABP4/aP2 in regulating macrophage redox signaling and inflammasome activation.
  • To elucidate the mechanistic link between FABP4/aP2, redox capacity, and inflammation in obesity.

Main Methods:

  • Utilized FABP4/aP2 knockout (KO) mouse models and FABP4/aP2 inhibitor-treated cells.
  • Assessed systemic redox capacity, protein oxidation (specifically mitochondrial cysteine residues), and antioxidant enzyme expression (SOD2, catalase, MSR A, 20S proteasome).
  • Evaluated the mitochondrial unfolded-protein response (mtUPR) and inflammasome activation markers (caspase-1, NLRP3, IL-1β).

Main Results:

  • FABP4/aP2 ablation reduced cellular protein sulfhydryl oxidation and mitochondrial protein cysteine oxidation.
  • KO macrophages showed upregulated antioxidants (SOD2, catalase, MSR A) and proteasome subunits, alongside attenuated mtUPR.
  • Inflammasome activation, evidenced by cleaved caspase-1, NLRP3, and IL-1β secretion, was significantly reduced in FABP4/aP2-deficient macrophages.

Conclusions:

  • FABP4/aP2 plays a critical role in regulating macrophage redox signaling and inflammasome activation.
  • The absence of FABP4/aP2 mitigates obesity-induced inflammation by enhancing antioxidant defenses and reducing oxidative stress.
  • UCP2 is a key mediator in the pathway through which FABP4/aP2 influences macrophage inflammatory responses.
Keywords:
FABPUCP2inflammasomeinflammationmitochondrial metabolismobesity

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