Up-regulation of human monocyte CD163 upon activation of cell-surface Toll-like receptors

Abstract: The hemoglobin (Hb) scavenger re-ceptor, CD163, is a cell-surface glycoprotein that is expressed exclusively on monocytes and macrophages. It binds and internalizes haptoglo-bin-Hb complexes and has been implicated in the resolution of inflammation. Furthermore, the regulation of CD163 during an innate immune response implies an important role for this mol-ecule in the host defense against infection. LPS, derived from the outer membrane of Gram-neg-ative bacteria, activates TLR4 to cause acute shedding of CD163 from human monocytes, fol-lowed by recovery and induction of surface CD163 to higher levels than observed on un-treated monocytes. We now report that the TLR2 and TLR5 agonists—Pam3Cys and bacte-rial flagellin—have similar effects on CD163 sur-face expression. Up-regulation of CD163 follow-ing treatment of human PBMC with TLR2, TLR4, and TLR5 agonists parallels increased production of IL-6 and IL-10, and neutralization of IL-6 and/or IL-10 blocks CD163 up-regula-tion. Furthermore, simultaneous stimulation of TLR2 or TLR5 in combination with TLR4 acti-vation results in enhanced up-regulation of CD163. It is notable that exogenous recombi-nant IFN- (rIFN-) suppresses cell-surface, TLR-mediated IL-10 production as well as CD163 up-regulation. Sustained down-regula-tion of CD163 mediated by rIFN- can be par-tially rescued with exogenous rIL-10 but not with exogenous rIL-6. This divergent regulation of CD163 by cytokines demonstrates that human monocytes react differently to infectious signals depending on the cytokine milieu they encoun-ter. Thus, surface CD163 expression on mono-nuclear phagocytes is a carefully regulated com-ponent of the innate immune response t