Macrophage polarization phenotype regulates adiponectin receptor expression and adiponectin anti-inflammatory response.
Adiponectin (APN), a pleiotropic adipokine that exerts anti-inflammatory, antidiabetic, and antiatherogenic effects through its receptors (AdipoRs), AdipoR1 and AdipoR2, is an important therapeutic target. Factors regulating AdipoR expression in monocyte/macrophages are poorly understood, and the significance of polarized macrophage activation in controlling AdipoR expression and the APN-mediated inflammatory response has not been investigated. The aim of this study was to investigate whether the macrophage polarization phenotype controls the AdipoR expression and APN-mediated inflammatory response. With the use of mouse bone marrow and peritoneal macrophages, we demonstrate that classical activation (M1) of macrophages suppressed (40-60% of control) AdipoR expression, whereas alternative activation (M2) preserved it. Remarkably, the macrophage polarization phenotypes produced contrasting inflammatory responses to APN (EC50 5 µg/ml). In M1 macrophages, APN induced proinflammatory cytokines, TNF-α, IL-6, and IL-12 (>10-fold of control) and AdipoR levels. In contrast, in M2 macrophages, APN induced the anti-inflammatory cytokine IL-10 without altering AdipoR expression. Furthermore, M1 macrophages adapt to a cytokine environment by reversing AdipoR expression. APN induced AdipoR mRNA and protein expression by up-regulating liver X receptor-α (LXRα) in macrophages. These results provide the first evidence that macrophage polarization is a key determinant regulating AdipoR expression and differential APN-mediated macrophage inflammatory responses, which can profoundly influence their pathogenic role in inflammatory and metabolic disorders.
*Division of Endocrinology, Diabetes & Hypertension andDivision of Cardiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA; andNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Caroline M W
CM
van Stijn
*Division of Endocrinology, Diabetes & Hypertension andDivision of Cardiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA; andNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Jason
J
Kim
*Division of Endocrinology, Diabetes & Hypertension andDivision of Cardiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA; andNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Aldons J
AJ
Lusis
*Division of Endocrinology, Diabetes & Hypertension andDivision of Cardiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA; andNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Grant D
GD
Barish
*Division of Endocrinology, Diabetes & Hypertension andDivision of Cardiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA; andNorthwestern University Feinberg School of Medicine, Chicago, Illinois, USA rtangirala@mednet.ucla.edu.
Rajendra K
RK
Tangirala
D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D016753:Interleukin-10 / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010641:Phenotype; D054419:Receptors, Adiponectin / Q000378:metabolism*
C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; D016207:Cytokines; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D054419:Receptors, Adiponectin; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D016753:Interleukin-10
adipokines; inflammation; macrophage activation; metabolic disorder; nuclear receptors