title: Haptoglobin Genotype-Dependent Anti-Inflammatory Signaling in CD163(+) Macrophages.
abstract: Intraplaque hemorrhage causes adaptive remodelling of macrophages towards a protective phenotype specialized towards handling iron and lipid overload, denoted Mhem. The Mhem phenotype expresses elevated levels of hemoglobin (Hb) scavenger receptor, CD163, capable of endocytosing pro-oxidant free Hb complexed to acute phase protein haptoglobin (Hp). It is notable that individuals homozygous for the Hp 2 allele (a poorer antioxidant) are at increased risk of cardiovascular disease compared to the Hp 1 allele. In this study, we examined whether scavenging of polymorphic Hp:Hb complexes differentially generated downstream anti-inflammatory signals in cultured human macrophages culminating in interleukin (IL)-10 secretion. We describe an anti-inflammatory signalling pathway involving phosphatidylinositol-3-kinase activation upstream of Akt phosphorylation (pSer473Akt) and IL-10 secretion. The pathway is mediated specifically through CD163 and is blocked by anti-CD163 antibody or phagocytosis inhibitor. However, levels of pSer473Akt and IL-10 were significantly diminished when scavenging polymorphic Hp2-2:Hb complexes compared to Hp1-1:Hb complexes (P < 0.05). Impaired anti-inflammatory macrophage signaling through a CD163/pAkt/IL-10 axis may thus represent a possible Hp2-2 disease mechanism in atherosclerosis.
authors.affiliation: Edmund Cohen Laboratory for Vascular Research, Chronic Disease Research Centre, The University of the West Indies Bridgetown BB11115, Barbados ; Eric Bywaters Centre for Vascular Inflammation, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
authors.forename: R Clive
authors.initials: RC
authors.lastname: Landis
authors.forename: Pandelis
authors.initials: P
authors.lastname: Philippidis
authors.forename: Jan
authors.initials: J
authors.lastname: Domin
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Boyle
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard