Adiponectin modulates inflammatory reactions via calreticulin receptor–dependent clearance of early apoptotic bodies
Yukihiro Takemura, … , Shinji Kihara, Kenneth Walsh
Yukihiro Takemura, … , Shinji Kihara, Kenneth Walsh
Published February 1, 2007
Citation Information: J Clin Invest. 2007;117(2):375-386. https://doi.org/10.1172/JCI29709.
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Research Article Immunology

Adiponectin modulates inflammatory reactions via calreticulin receptor–dependent clearance of early apoptotic bodies

Abstract

Obesity and type 2 diabetes are associated with chronic inflammation. Adiponectin is an adipocyte-derived hormone with antidiabetic and antiinflammatory actions. Here, we demonstrate what we believe to be a previously undocumented activity of adiponectin, facilitating the uptake of early apoptotic cells by macrophages, an essential feature of immune system function. Adiponectin-deficient (APN-KO) mice were impaired in their ability to clear apoptotic thymocytes in response to dexamethasone treatment, and these animals displayed a reduced ability to clear early apoptotic cells that were injected into their intraperitoneal cavities. Conversely, adiponectin administration promoted the clearance of apoptotic cells by macrophages in both APN-KO and wild-type mice. Adiponectin overexpression also promoted apoptotic cell clearance and reduced features of autoimmunity in lpr mice whereas adiponectin deficiency in lpr mice led to a further reduction in apoptotic cell clearance, which was accompanied by exacerbated systemic inflammation. Adiponectin was capable of opsonizing apoptotic cells, and phagocytosis of cell corpses was mediated by the binding of adiponectin to calreticulin on the macrophage cell surface. We propose that adiponectin protects the organism from systemic inflammation by promoting the clearance of early apoptotic cells by macrophages through a receptor-dependent pathway involving calreticulin.

Authors

Yukihiro Takemura, Noriyuki Ouchi, Rei Shibata, Tamar Aprahamian, Michael T. Kirber, Ross S. Summer, Shinji Kihara, Kenneth Walsh

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Figure 7

Adiponectin interacts with calreticulin on the macrophage cell surface.

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Adiponectin interacts with calreticulin on the macrophage cell surface. ...
(A) Calreticulin is immunoprecipitated by histidine-tagged adiponectin (APN) from detergent-solubilized THP-1 membranes. Membrane fractions were incubated in the presence or absence of polyhistidine-APN and then precipitated with nickel resin. The resin was then treated with a molar excess of histidine to release precipitated proteins, and this material was subjected to SDS-PAGE followed by immunoblot analysis with anti-calreticulin (anti-CRT) and anti-adiponectin (anti-APN) antibodies. WB, Western blot. (B) Adiponectin prepared from E. coli (E-APN) was immunoprecipitated from detergent-solubilized THP-1 membranes by anti-calreticulin antibodies. THP-1 membrane fractions were incubated in the presence or absence of polyhistidine APN and then subjected to immunoprecipitation with anti-CRT or control IgG. Immunoprecipitated material was then subjected to SDS-PAGE, and Western blot analysis was performed with anti-APN or anti-CRT antibodies. (C) Adiponectin inhibits the binding of anti-calreticulin antibody to macrophages. THP-1 macrophages were preincubated with 200 μg/ml adiponectin (red) or vehicle (blue) for 60 minutes followed by incubation with anti-calreticulin antibody (10 μg/ml) for 60 minutes. Cells incubated with chicken IgY followed by treatment with FITC-conjugated secondary antibody served as control. Cells were then incubated with FITC-conjugated secondary antibody to anti-calreticulin antibody and analyzed by flow cytometry. *P < 0.05 versus vehicle (n = 3).