Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging

Abstract

Haptoglobin, the haptoglobin-hemoglobin receptor CD163, and the heme oxygenase-1 are proteins with a well-established function in the clearance and metabolism of "free" hemoglobin released during intravascular hemolysis. This scavenging system counteracts the potentially harmful oxidative and NO-scavenging effects associated with "free" hemoglobin, and, furthermore, elicits an anti-inflammatory response. In the late primate evolution, haptoglobin variants with distinct functions have arisen, including haptoglobin polymers and the haptoglobin-related protein. The latter associates with a subspecies of high-density lipoprotein (HDL) particles playing a crucial role in the innate immunity against certain trypanosome parasites. Recent studies have elucidated this fairly sophisticated immune defense mechanism that takes advantage of a trypanosomal haptoglobin-hemoglobin receptor evolved to supply the parasite with heme. Because of the high resemblance between haptoglobin and haptoglobinrelated protein, the receptor also takes up the complex of hemoglobin and the HDL- IntroductionHaptoglobin (Hp), an abundant acute phase plasma glycoprotein of the ␣ 2 -globulin fraction, was initially reported in 1938 by Polonovski and Jayle to be a "plasma substance" that binds hemoglobin (Hb). 1 In agreement with this initial characterization and its designation as "haptoglobin" (Greek: haptein, "to bind" ϩ [hemo]globin), Hp has a well-established role in binding of "free" Hb released into the circulation during the process of intravascular hemolysis. By capturing the liberated Hb, Hp protects against toxic effects associated with Hb, and it facilitates Hb clearance through endocytosis by the macrophage scavenger receptor CD163. 2 Later studies of human and primate plasma revealed variant forms of Hp as well as the existence of an Hp-related protein (Hpr) that recently has been shown also to bind Hb. As highlighted in this review, novel functions of Hp depend on high-affinity interactions with Hb and lipoprotein and subsequent receptor recognition of the resulting complexes. Toxicity of hemoglobin released during intracellular hemolysisIntravascular hemolysis, which accounts for approximately 10% to 20% of total red blood cell destruction, 3 changes Hb from being an intracellular O 2 /CO 2 transporter to a highly toxic substance in plasma. This toxicity arises from the heme iron, which can react with endogenous hydrogen peroxide to produce free radicals, which in turn may cause severe oxidative tissue damage, 4 particularly in the kidney. 5 In addition to the oxidative toxicity of Hb, Hb is a potent scavenger of nitric oxide (NO), a signaling molecule that functions as a critical regulator of smooth muscle relaxation, endothelial adhesion molecule expression, and platelet activation and aggregation. 6,7 The reaction of Hb with NO is fast and irreversible, leading to the production of nitrate and methemoglobin. If allowed to occur, this Hbmediated consumption of vascular NO, referred to as NOscavenging, thus limits the bioavailabili...

Extracellular Chaperones and Proteostasis

“…There are many reports describing the effects of clusterin, haptoglobin and α 2 M on the immune system (59,(176)(177)(178)(179)(180). Some of these, such as the ability of α 2 M to enhance antigen presentation (91) and haptoglobin-facilitated clearance of hemoglobin (180), clearly fall outside of the scope of this review and as such, will not be discussed here.…”

The Conserved Scavenger Receptor Cysteine-Rich Superfamily in Therapy and Diagnosis

“…Besides the potential use of sCD163 as a marker of macrophage activity in disease, it has also been proposed to exploit CD163 in therapy by using this receptor for targeting drugs to macrophages (Nielsen and Moestrup, 2009). This has rather intriguing perspectives because macrophages, as the main producers of TNF-␣ and other proinflammatory cytokines, are a main effector cell in many inflammatory diseases such as rheumatoid arthritis and chronic intestinal inflammation.…”

Acute Phase Proteins: Structure and Function Relationship

“…Ca 2+ and phosphocholine bind to the B (binding) face of the pentameric ring, whereas the other A ( -helix) face binds to macromolecular ligands such as C1q. The complex between Hp and Hemoglobin has been studied for decades and represents one of the strongest non-covalent interactions reported in plasma (Nielsen & Moestrup, 2009). Hp also binds apolipoprotein A-I (ApoA-I), and impairs its stimulation of lecithin: cholesterol acyltransferase (LCAT) which plays a major role in reverse cholesterol transport (Cigliano et al, 2009).…”