The rat macrophage scavenger receptor CD163: Expression, regulation and role in inflammatory mediator production

Abstract

The monoclonal antibody ED2 is widely used to define macrophages $(\mathrm{m}\varphi )$ in the rat. We have recently identified the ED2 antigen as the rat CD163 glycoprotein. CD163 is a member of the scavenger receptor cysteine-rich group B (SRCR-B) family and functions as a scavenger receptor for hemoglobin–haptoglobin complexes. Moreover, CD163 has also been indicated as a marker for alternatively activated $\mathrm{m}\varphi$. In the current study, we identify rat CD163/ED2-antigen as a marker for mature tissue $\mathrm{m}\varphi$. Rat CD163 is constitutively expressed on most subpopulations of mature tissue $\mathrm{m}\varphi$, including splenic red pulp $\mathrm{m}\varphi$, thymic cortical $\mathrm{m}\varphi$, Kupffer cells in the liver, resident bone marrow $\mathrm{m}\varphi$ and central nervous system perivascular and meningeal $\mathrm{m}\varphi$, but is apparently absent from monocytes. Rat CD163 expression can be promoted by glucocorticoids, and this can be further enhanced by IL4. Finally, engagement of rat CD163 on peritoneal $\mathrm{m}\varphi$ induces the production of pro-inflammatory mediators, including NO, IL-$1\beta$, IL-6 and TNF-$\alpha$. Collectively, our findings identify rat CD163 as a broadly expressed macrophage scavenger receptor that may play a role in the activation of $\mathrm{m}\varphi$ during hemolytic and/or inflammatory conditions.

Introduction

Macrophages $(\mathrm{m}\varphi )$ play important roles in normal and during various pathological conditions, such as (autoimmune) inflammation, infection, atherosclerosis and cancer. The major activities of $\mathrm{m}\varphi$, including phagocytosis and the production of inflammatory mediators, are controlled by surface receptors.

The surface glycoprotein CD163 is a member of the scavenger receptor cysteine-rich group B (SRCR-B) family and human CD163 has been shown to function as a scavenger receptor for hemoglobin–haptoglobin complexes and this may contribute to the clearance of toxic-free hemoglobin from the circulation and tissues (Law et al., 1993; Kristiansen et al., 2001). Engagement of human CD163 also results in the production of pro- and anti-inflammatory cytokines suggesting a potential role in host defense and/or inflammation (Van den Heuvel et al., 1999; Philippidis et al., 2004; Ritter et al., 2000). Human CD163 is expressed on tissue $\mathrm{m}\varphi$ and on a subset of monocytes (Van den Heuvel et al., 1999; Radzun et al., 1987). Expression on monocytes can be upregulated by glucocorticoids and anti-inflammatory cytokines, such as IL10 (Van den Heuvel et al., 1999; Hogger et al., 1998; Buechler et al., 2000). Consequently, CD163 has been indicated as a possible marker for so-called alternatively activated $\mathrm{m}\varphi$, which have been suggested to possess immune-suppressive activity (Gordon, 2003; Mosser, 2002; Verreck et al., 2006). Thus far, little is known about the expression and function of CD163 in other species, such as rodents. We have recently demonstrated by purification and peptide sequencing that the rat ED2 antigen represents the rat ortholog of CD163 (Fabriek et al., submitted). Our previous analysis has demonstrated that rat CD163/ED2-antigen is expressed on subsets of tissue $\mathrm{m}\varphi$ (Dijkstra et al., 1985; Damoiseaux et al., 1989; Barbe et al., 1990).

In the present study, we extend these findings and confirm that rat CD163 is a marker for most mature tissue $\mathrm{m}\varphi$. Furthermore, we evaluate the regulation of rat CD163 by glucocorticoids and IL4. Finally, we provide evidence that rat CD163 upon ligation can trigger the production of pro-inflammatory mediators in $\mathrm{m}\varphi$.