Adiponectin primes human monocytes into alternative anti-inflammatory M2 macrophages.
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.
Lovren
Fina
F
Division of Cardiac Surgery, Keenan Research Centre in Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada.
Pan
Yi
Y
Quan
Adrian
A
Szmitko
Paul E
PE
Singh
Krishna K
KK
Shukla
Praphulla C
PC
Gupta
Milan
M
Chan
Lawrence
L
Al-Omran
Mohammed
M
Teoh
Hwee
H
Verma
Subodh
S
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D052242:Adiponectin; D047495:PPAR gamma; D055372:AMP-Activated Protein Kinases