Adiponectin & Apoptotic Cell Clearance: R&D Systems

Adiponectin, also known as Acrp30, is an adipocyte-specific secreted protein with wide ranging effects on metabolism and inflammation. Adiponectin regulates glucose and fatty acid metabolism, insulin responsiveness, and adipocyte differentiation.¹ It has multiple anti-inflammatory properties (Box 1) that distinguish it from other adipocytokines such as leptin, resistin, and visfatin.² These various functions are mediated by the interaction of adiponectin with the receptors AdipoR1, AdipoR2, and, potentially, with cadherin-13/T-cadherin.^3,⁴ Adiponectin is the focus of much clinical interest for its involvement in the development of type II diabetes, obesity, and cardiovascular disease.¹

Box 1
Anti-Inflammatory Effects of Adiponectin²

Decreased production of CXCL8,
IFN-gamma, IL-6, and TNF-alpha
Increased production of IL-1ra and
IL-10
Decreased activation of NF kappa B
Downregulation of vasular endothelial cell adhesion molecules
Inhibition of macrophage-foam cell development

Adiponectin consists of a globular domain and a collagen-like tail, both of which contribute to its association into multiple low, middle, and high molecular weight multimeric forms.⁵ Adiponectin complexes are structurally similar to C1q and the collectins, molecules that participate in the clearance of apoptotic cells by macrophages.⁶ The high circulating concentration of these molecules in the blood enables them to bind ligands with high avidity, suggesting regulatory functions.

Inspired by the structural parallels between these molecules, Takemura et al.⁷ recently elucidated how adiponectin also mediates the in vivo clearance of apoptotic cells, in a manner analagous to C1q and the collectins. In this mechanism, adiponectin preferentially binds to apoptotic blebs on dying cells, leading to phagocytosis by monocyte-derived macrophages. This adiponectin-dependent engulfment is restricted to early apoptotic cells, suggesting signal transduction via membrane receptors. Interestingly, this opsonization does not require AdipoR1, AdipoR2, or cadherin-13 on the target cells. Rather, the authors identify the apoptotic cell determinant as calreticulin. Calreticulin, typically identified as a calcium-binding chaperone of the endoplasmic reticulum⁸, has been shown to be upregulated in patches on the surface of apoptotic cells.⁹ This calreticulin clustering is coordinated with a decrease in CD47, a molecule whose interaction with macrophage SIRP-a prevents phagocytosis of viable cells (Figure 1). In addition, calreticulin is expressed on the macrophage in association with the phagocytic receptor LRP/CD91.^5,^9,¹⁰ The interaction of adiponectin with calreticulin on both the apoptotic cell and the macrophage is critical for the apoptotic cell clearance, as experimental knockdown of either calreticulin or LRP blocks adiponectin-dependent phagocytosis.⁵ Apoptotic cells opsonized by C1q, or the collectins MBL, SP-A, and SP-D, are cleared by a similar mechanism involving calreticulin and LRP.^9,¹⁰ Such molecular redundancy is consistent with the partial decrease in apoptotic cell clearance observed in adiponectin knockout mice.⁵

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Figure 1. Viable cells express CD47 which binds SIRP-alpha on macrophages to prevent phagocytosis. Early apoptotic cells downregulate CD47 and upregulate calreticulin in patches. Adiponectin recognizes calreticulin and promotes LRP-dependent clearance of apoptotic cells.

The recognition and clearance of apoptotic cells helps prevent systemic inflammation.¹² These dying cells, if not cleared safely, would become necrotic, disintegrate, and release pro-inflammatory molecules. The failure to clear apoptotic cells has also been linked to the production of auto-antibodies.¹² Adiponectin-deficient mice, in fact, show increased severity of autoimmune symptoms.⁵ Apoptotic cell clearance is a novel function of adiponectin that operates in tandem with adiponectin's other anti-inflammatory functions.