The obesity and inflammatory marker haptoglobin attracts monocytes via interaction with chemokine (C-C motif) receptor 2 (CCR2)

Abstract

BackgroundObesity is a chronic low inflammatory state. In the obesity condition the white adipose tissue (WAT) is massively infiltrated with monocytes/macrophages, and the nature of the signals recruiting these inflammatory cells has yet to be fully elucidated. Haptoglobin (Hp) is an inflammatory marker and its expression is induced in the WAT of obese subjects. In an effort to elucidate the biological significance of Hp presence in the WAT and of its upregulation in obesity we formulated the hypothesis that Hp may serve as a macrophage chemoattractant.ResultsWe demonstrated by chemotaxis assay that Hp is able to attract chemokine (C-C motif) receptor 2 (CCR2)-transfected pre-B lymphocytes and monocytes in a dose-dependent manner. Moreover, Hp-mediated migration of monocytes is impaired by CCR2-specific inhibition or previous cell exposure to monocyte chemoattractant protein 1 (MCP1) (also known as CCR2 ligand or chemokine (C-C motif) ligand 2 (CCL2)). Downstream effects of Hp/CCR2 interaction were also investigated: flow cytometry proved that monocytes treated with Hp show reduced CCR2 expression on their surface; Hp interaction induces calcium release that is reduced upon pretreatment with CCR2 antagonist; extracellular signal-regulated kinase (ERK)1/2, a signal transducer activated by CCR2, is phosphorylated following Hp treatment and this phosphorylation is reduced when cells are pretreated with a specific CCR2 inhibitor. Consistently, blocking the ERK1/2 pathway with U0126, the selective inhibitor of the ERK upstream mitogen-activated protein (MAP)-ERK kinase (MEK), results in a dramatic reduction (by almost 100%) of the capability of Hp to induce monocyte migration.ConclusionsOur data show that Hp is a novel monocyte chemoattractant and that its chemotactic potential is mediated, at least in part. by its interaction with CCR2.

Proteomic Changes Induced by Effective Chemopreventive Ratios of n-3:n-6 Fatty Acids and Tamoxifen against MNU-Induced Mammary Cancer in the Rat

“…Haptoglobin is an acute-phase protein synthesized and dispersed by the liver, muscle, and adipose tissue and has a role in inflammatory states, such as obesity (42). Some studies (43) but not others (44,45) have reported an increase in the level of this protein in the serum of breast cancer patients.…”

Acute phase proteins in ruminants

“…For SAA3, the inducible adipocytederived isoform of SAA, a role in monocyte recruitment and adhesion acting in concert with hyaluronan but independently from monocyte chemoattractant protein-1 (MCP-1) has been documented [149]. Similarly, Hp has been shown to act as monocyte attractant [150].…”

Effect of vitamin A deficiency on the immune response in obesity

“…Vitamin A deficiency is highly prevalent in obesity and this may produce inadequate Th1:Th2 ratio, increased leptin concentrations, and elevate proinflammatory cytokines levels (18,106,107) . Vitamin A deficiency reduces not only RA levels but also retinaldehyde, and therefore may be contributing to fat deposition.…”