CD163, a Hemoglobin/Haptoglobin Scavenger Receptor, After Intracerebral Hemorrhage: Functions in Microglia/Macrophages V
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COMMENTARY
CD163, a Hemoglobin/Haptoglobin Scavenger Receptor, After Intracerebral Hemorrhage: Functions in Microglia/Macrophages Versus Neurons Thomas Garton 1 & Richard F. Keep 1 & Ya Hua 1 & Guohua Xi 1
Received: 27 March 2017 / Accepted: 31 March 2017 # Springer Science+Business Media New York 2017
Abbreviations ADAM-17 A disintegrin and metalloproteinase domain-17 ICH Intracerebral hemorrhage IL-10 Interleukin-10 sCD163 Soluble CD163 EVExtracellular vesicle CD163 CD163 HO Heme oxygenase NeuN Neuron-specific nuclear protein SRCR Scavenger receptor cysteine-rich
Introduction Following intracerebral hemorrhage (ICH), clot-derived factors cause secondary brain damage. In particular, hemoglobin released during erythrolysis has been the focus of a large body of research due to its iron-containing heme cofactors. When not bound to O2, heme-bound iron exists in a ferrous (Fe2+) state capable of performing radical chemistry to create dangerous reactive oxygen species. Several studies have highlighted the hemoglobin-induced damage caused to neuronal populations during hemorrhagic stroke, suggesting the existence of pathways by which hemoglobin-associated iron can enter neurons and inflict oxidative injury [1–3]. While there are several known mechanisms by which free iron and heme can enter cells, the number of known hemoglobin uptake
* Guohua Xi [email protected] 1
Department of Neurosurgery, University of Michigan, R5018 Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI, USA
mechanisms is limited. The best characterized is CD163, long thought to be a marker of monocytes/macrophages. Recent evidence shows that CD163 can also be expressed in neuronal populations following ICH, providing a mechanism for hemoglobin uptake into neurons [2, 4]. This commentary discusses the potential beneficial roles of CD163 in microglia/ macrophages after ICH and compares them to potentially detrimental effects the receptor may have in neurons. CD163 Function A 130-kDa member of the scavenger receptor cysteine-rich (SRCR) superfamily, CD163 is a single membrane-pass protein with nine extracellular domains [5]. Kristiansen et al. identified CD163 as a scavenger receptor for haptoglobinhemoglobin complexes [6]. Haptoglobin binds hemoglobin with exceptionally high affinity (Kd~1 pM), and in addition to being involved in the cellular uptake of hemoglobin via CD163, it also markedly reduces the ability of hemoglobin to participate in oxidative reactions [7]. Systemically, the CD163-mediated internalization of haptoglobin-hemoglobin complexes into macrophages is very important in the clearance of hemoglobin released after red blood cell lysis [6]. There is some evidence that CD163 can bind free hemoglobin that has not yet been scavenged by haptoglobin, albeit at a lower affinity. This may occur during hemolytic conditions where haptoglobin is saturated [8] or, potentially, in tissues with low haptoglobin expression (e.g., brain). CD163 has additional functions that may be distinct from its ability to scavenge he
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