| CD163 is a monocyte- and macrophage-specific surface glycoprotein proposed to function in the maintenance of homeostasis and the resolution of inflammation. CD163 binds hemoglobin-haptoglobin complexes implicating this receptor as a hemoglobin scavenger receptor. Hemolysis of senescent red blood cells occurs constitutively at low levels and can be exacerbated by infection or genetic predisposition. Clearance of hemoglobin allows monocytes to recycle hemoglobin-derived iron and may be one mechanism whereby CD163 exerts an anti-inflammatory function, as free hemoglobin is toxic and can exacerbate inflammation.;This thesis addresses the pathophysiologic regulation of CD163 and demonstrates that multiple pathogen-associated molecular patterns (PAMPs) derived from a diverse range of microbes stimulate CD163 shedding through activation of different classes of pattern recognition receptors (PRR), including Toll-like receptors (TLRs). Interestingly, TLR-mediated activation of CD163 shedding is selective for extracellular TLR agonists. Activation of the beta-glucan receptor and the cytosolic receptor Nod2 also stimulate CD163 shedding. Thus, soluble CD163 is generated following activation of PRRs, and may function in the innate immune response to infection.;This thesis highlights how monocyte activation by different classes of PRRs alters the ability of these cells to respond to exogenous anti-inflammatory mediators. Following activation of extracellular TLRs, surface CD163 is induced to levels above those on untreated monocytes. This superinduction parallels increased production of interleukin (IL)-6 and IL-10, and neutralization of IL-6 and/or IL-10 blocks CD163 superinduction. In contrast, activation of non-TLR PRRs does not cause CD163 superinduction and can alter the ability of monocytes to respond to IL-10 and dexamethasone.;The extensive regulation of CD163 by PRR agonists implicates functions for this molecule beyond hemoglobin scavenging. This thesis demonstrates that production of soluble CD163 is a common early innate immune response to a diverse range of microbes. We hypothesize that binding of soluble CD163 to free hemoglobin may limit the ability of pathogens to acquire free hemoglobin as a source of iron. Furthermore, decreased surface expression of CD163 may limit the internalization of hemoglobin into mononuclear phagocytes, thus reducing its contribution to the intracellular labile iron pool and limiting the availability of iron to intracellular pathogens. |
