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 4

B6/lpr mice deficient in adiponectin display impaired clearance of apoptotic cells and increased systemic inflammation.

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B6/lpr mice deficient in adiponectin display impaired clearance of apopt...
(A) Impaired clearance of apoptotic cells by peritoneal macrophages in APN-KO/lpr mice compared with APN-KO and lpr mice. Experiments were conducted with the indicated strains of mice. Phagocytosis of apoptotic Jurkat cells was assessed by flow cytometric analysis of F4/80- and TAMRA, SE–positive cells as described in the Figure 1C legend. *P < 0.05 versus B6/lpr APN-KO (n = 4–6). (B) APN-KO/lpr mice have larger submandibular lymph nodes compared with lpr mice. Inset shows a representative photograph of submandibular lymph nodes from each strain of mouse at the age of 20 weeks. Scale bar: 5 mm. Submandibular lymph nodes were excised from the indicated strains of mice at 12 or 20 weeks and weighed. *P < 0.05 versus lpr (n = 6–14). (C) Adiponectin deficiency increases the frequency of apoptotic cells in lymph nodes of B6.lpr mice. Mice were sacrificed at 12 or 20 weeks of age, and TUNEL-positive cells in sections of submandibular lymph nodes were assessed. ND, not detectable. **P < 0.01 versus lpr (n = 6–14). (D) Adiponectin deficiency increases autoreactive antibody titer in B6.lpr mice. ANA titers and anti-dsDNA antibody titers in the sera of each strain of mouse were determined at 12 or 20 weeks of age. **P < 0.01 versus lpr (n = 3–14). (E) Adiponectin deficiency promotes kidney disease in B6.lpr mice. Glomerular tuft volume was determined in histological sections of kidney from the indicated strains of 20-week-old mice. Photographs show representative glomeruli. The calculated glomerular tuft volume of control is 1.1 × 105 ± 0.1 × 105 μm3. Scale bar: 50 μm. **P < 0.01 versus lpr. The daily excretion of urinary albumin was determined immediately prior to sacrifice. *P < 0.05 versus lpr (n = 4–10).