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.

Obesity as a risk factor for Alzheimer’s disease: the role of adipocytokines

“…Adiponectin (ACRP30) is the most abundant adipocytokine, presenting in plasma in globular, trimer, hexamer and highmolecular weight (HMW) isoforms (Fruebis et al 2001;Takemura et al 2007). Unlike leptin, adiponectin secretion is inversely correlated with fat mass and promotes antiinflammatory, antiangiogenic, antiatherogenic and vasodilatory action, exerting also beneficial effects on lipid and glucose profiles (Gustafson 2010).…”

“…Tumor necrosis factor-alpha (TNF-α) levels strongly correlate with BMI (Takemura et al 2007) and have been implicated in the demential process, though inconsistently (Une et al 2011). Guerreiro et al (2007) showed that in MCI and AD patients there was a significant raise in the percentage of monocytes producing pro-inflammatory interleukins (IL-1β, IL-6, IL-12) and TNF-α when compared with healthy controls.…”

Systemic Adiponectin Malfunction as a Risk Factor for Cardiovascular Disease

“…However, as Tcadherin lacks an intracellular domain, the specific biologic function of any Ad/T-cadherin interaction remains unknown. Calreticulin (CRT), a multifunctional chaperone protein binding calcium ions, in concert with its adaptor protein CD91, has been identified by Walsh's group (40,60) to be yet another receptor for Ad. Ad's interaction with CRT/CD91 has been shown to exert endothelial anti-inflammatory and vasculoprotective effects.…”

From regulation of dying cell engulfment to development of anti-cancer therapy

“…25 Adiponectin, an abundant circulating adipocyte-derived cytokine that is decreased in obese individuals, can opsonize apoptotic cells and promote engulfment through interaction with calreticulin and CD91 on the phagocyte surface. 26 Interestingly, calreticulin even mediates uptake of viable cells if the interactions between CD47 on the viable target cell and signal regulator protein-a (SIRPa,) on the phagocyte are disrupted. 13 The former is an integrin-associated protein, and the latter is a heavily glycosylated transmembrane protein with an immunoreceptor tyrosine-based inhibition motif domain.…”