Role of Haptoglobin in Abdominal Aortic Aneurysm

Abstract

Haptoglobin (abbreviated as Hp) is a plasmatic protein encoded by the HP gene (OMIM*140100, gene map locus 16q22.1). Its main function in blood plasma is binding free hemoglobin (Hb) released from erythrocytes with high affinity and thereby inhibiting its oxidative activity. The Hp-Hb complex is then removed by the reticuloendothelial system (mostly the spleen). Hp is widely used in clinical settings where the Hp assay is implemented to screen for and monitor intravascular hemolytic anemia [1]. In intravascular hemolytic anemia, free Hb is released into the circulation, and hence Hp binds the Hb. This causes a decline in Hp levels. Conversely, in extravascular hemolysis, the reticuloendothelial system, especiallysplenic monocytes, phagocytose the erythrocytes, and Hb is not released into the circulation; hence, the Hp levels are normal. Thus, Hp is a potent antioxidant playing a scavenging role for the toxic free Hb that accumulates during acute-phase inflammatory reactions [1]. However, importantly, Hp also exerts a direct angiogenic, antiinflammatory, and immunomodulatory function in extravascular tissues and body fluids. In fact, in response to various stimuli, Hp is able to migrate through vessel walls and is expressed in different tissues [2]. Furthermore, Hp can be released from neutrophil granulocytes at sites of injury or inflammation and locally dampens tissue damage [3]. Hp receptors include CD163 expressed on the monocyte-macrophage system and CD11b (CR3) found on granulocytes, natural killer cells, and in small lymphocyte subpopulations [4, 5]. Hp has also been shown to bind to the majority of CD4+ and CD8+ T cells, directly inhibiting their proliferation and modifying the T helper (Th) Th1/Th2 balance [6]. Notably, Hp inhibits the capacity of epidermal Langerhans cells to activate naive T cells, and abundant Hp has been detected in cytoplasmic compartments of Langerhans cells and in neutrophils [7, 8]. Also, Hp binds to mast cells through another, yet unidentified receptor, possibly modulating their function [9]. Lastly, HDL particles can become proinflammatory through direct interactions of Hp-Hb complexes with apolipoprotein A1 [10].