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. 2010 Sep;299(3):H656-63.
doi: 10.1152/ajpheart.00115.2010. Epub 2010 Jul 9.

Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages

Fina Lovren  1 , Yi Pan, Adrian Quan, Paul E Szmitko, Krishna K Singh, Praphulla C Shukla, Milan Gupta, Lawrence Chan, Mohammed Al-Omran, Hwee Teoh, Subodh Verma
Affiliations

Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages

Fina Lovren et al. Am J Physiol Heart Circ Physiol. 2010 Sep.

Abstract

Altered macrophage kinetics is a pivotal mechanism of visceral obesity-induced inflammation and cardiometabolic risk. Because monocytes can differentiate into either proatherogenic M1 macrophages or anti-inflammatory M2 macrophages, approaches that limit M1 while promoting M2 differentiation represent a unique therapeutic strategy. We hypothesized that adiponectin may prime human monocytes toward the M2 phenotype. Adiponectin promoted the alternative activation of human monocytes into anti-inflammatory M2 macrophages as opposed to the classically activated M1 phenotype. Adiponectin-treated cells displayed increased M2 markers, including the mannose receptor (MR) and alternative macrophage activation-associated CC chemokine-1. Incubation of M1 macrophages with adiponectin-treated M2-derived culture supernatant resulted in a pronounced inhibition of tumor necrosis factor-alpha and monocyte chemotactic protein-1 secretion. Activation of human monocytes into M2 macrophages by adiponectin was mediated, in addition to AMP-activated protein kinase and peroxisome proliferator-activated receptor (PPAR)-gamma, via PPAR-alpha. Furthermore, macrophages isolated from adiponectin knockout mice demonstrated diminished levels of M2 markers such as MR, which were restored with adiponectin treatment. We report a novel immunoregulatory mechanism through which adiponectin primes human monocyte differentiation into anti-inflammatory M2 macrophages. Conditions associated with low adiponectin levels, such as visceral obesity and insulin resistance, may promote atherosclerosis, in part through aberrant macrophage kinetics.

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Figures

Fig. 1.
Fig. 1.
mRNA levels of mannose receptor (MR, A), alternative macrophage activation-associated CC chemokine-1 (AMAC-1, B), and CD163 (C) in resting macrophages (RM), M2 macrophages, and macrophages in the presence of adiponectin (M2-Adipo) as measured by real-time PCR with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acting as the housekeeping gene; n = 7 experiments. *P < 0.05 vs. RM. †P < 0.05 vs. M2.
Fig. 2.
Fig. 2.
Representative histograms and quantification of allophycocyanin-MR-positive (A) and phycoerythrin-CD163-positive (B) RM, M2, and M2-Adipo macrophages as detected by flow cytometry; n = 3 experiments. *P < 0.05 vs. RM. †P < 0.05 vs. M2.
Fig. 3.
Fig. 3.
Cytokine and chemokine secretions from lipopolysaccharide (LPS)-activated M1 macrophages that had previously been exposed to medium from RM, M2, or M2-Adipo macrophage cultures; n = 4 experiments. *P < 0.05 vs. RM. †P < 0.05 vs. M2.
Fig. 4.
Fig. 4.
mRNA levels of MR, AMAC-1, and CD163 in vehicle- and adiponectin-treated RM (A), LPS-activated M1 macrophages (B), and acetylated low density lipoprotein (AcLDL)-activated foam cells (C) as measured by real-time PCR with GAPDH acting as the housekeeping gene; n = 4 experiments.
Fig. 5.
Fig. 5.
mRNA levels of AMP-activated protein kinase (AMPK) (A), peroxisome proliferator-activated receptor (PPAR)-α (B), MR (C), and AMAC-1 (D) in RM, M2, and M2-Adipo macrophages (incubated in the presence or absence of GW-6471) as measured by real-time PCR with GAPDH acting as the housekeeping gene; n = 4 experiments. *P < 0.05 vs. RM. †P < 0.05 vs. M2. ‡P < 0.05 vs. M2-Adipo.
Fig. 6.
Fig. 6.
Representative Western blots for phosphorylated (p) and total AMPK (A), PPAR-α and –γ (B), and phosphorylated and total NF-κB and IκB (C) in RM, M2, and M2-Adipo macrophages. Blots are representative of 4 independent experiments.
Fig. 7.
Fig. 7.
mRNA levels of MR (A) and CD163 (B) in peritoneal monocytes isolated from wild-type (Adipoq+/+) mice and adiponectin knockout (Adipoq−/−) littermates as measured by real-time PCR with GAPDH acting as the housekeeping gene. C: MR protein levels in peritoneal monocytes from Adipoq−/− mice as detected by Western blotting with actin acting as the housekeeping protein. Monocytes were cultured with IL-4 alone or in the presence of adiponectin or its vehicle for 3 days; n = 5 for A and B, n = 3 for C. *P < 0.05 vs. Adipoq+/+. †P < 0.05 vs. Adipoq−/−.
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