Heme released from heme-binding proteins on internal hemorrhage, hemolysis, myolysis, or other cell damage is highly toxic due to oxidative and proinflammatory effects. Complex formation with hemopexin, the high-affinity heme-binding protein in plasma and cerebrospinal fluid, dampens these effects and is suggested to facilitate cellular heme metabolism. Using a ligand-affinity approach, we purified the human hemopexin-heme receptor and identified it as the low-density lipoprotein receptor-related protein (LRP)/CD91, a receptor expressed in several cell types including macrophages, hepatocytes, neurons, and syncytiotrophoblasts. Binding experiments, including Biacore analysis, showed that hemopexin-heme complex formation elicits the high receptor affinity. Uptake studies of radio-labeled hemopexin-heme complex in LRP/CD91-expressing COS cells and confocal microscopy of the cellular processing of fluorescent hemopexin-heme complex established the ability of LRP/CD91 to mediate hemopexin-heme internalization resulting in cellular heme uptake and lysosomal hemopexin degradation. Uptake of hemopexin-heme complex induced LRP/CD91-dependent heme-oxygenase 1 mRNA transcription in cultured monocytes. In conclusion, hemopexin-heme complexes are removed by a receptor-mediated pathway showing striking similarities to the CD163-mediated haptoglobin-hemoglobin clearance in macrophages. Furthermore, the data indicate a hitherto unknown role of LRP/CD91 in inflammation. (Blood. 2005; 106:2572-2579)

CD163 is a hemoglobin scavenger receptor exclusively expressed in the monocyte‐macrophage system. A particularly high expression is seen in macrophages of the ‘alternative activation’ phenotype playing a major role in dampening the inflammatory response and in scavenging components of damaged cells. CD163‐mediated endocytosis of haptoglobin‐hemoglobin complexes formed upon red blood cell hemolysis leads to lysosomal degradation of the ligand protein and metabolism of heme by cytosolic heme oxygenase. In accordance with a stimulated expression of haptoglobin, CD163 and heme oxygenase‐1 during the acute phase response, there is evidence that this metabolic pathway regulates inflammation by at least two ways. First, CD163 is reported to directly induce intracellular signaling leading to secretion of anti‐inflammatory cytokines. Second and perhaps even more important, the CD163‐mediated delivery of hemoglobin to the macrophage may fuel an anti‐inflammatory response because heme metabolites have potent anti‐inflammatory effects. In addition to being present on the macrophage surface, continuous shedding of the extracellular domain of CD163 leads to substantial amounts of soluble receptor in plasma. An increased shedding is due to inflammatory stimuli, and a role for soluble CD163 in immune suppression has been proposed. Furthermore, recent data indicate that soluble CD163 may be a valuable diagnostic parameter for monitoring macrophage activation in inflammatory conditions.

CD163 is an endocytic receptor for haptoglobin-hemoglobin complexes and is expressed solely on macrophages and monocytes. As a result of ectodomain shedding, the extracellular portion of CD163 circulates in blood as a soluble protein (sCD163) at 0.7–3.9 mg/l in healthy individuals. The function of sCD163 is unknown, but during inflammation and macrophage activation, sCD163 levels increase acutely due to metalloproteinase-mediated cleavage near the cell membrane. It is now evident that sCD163 is very useful as a biomarker of macrophage activation in various inflammatory diseases, such as macrophage activation syndrome, sepsis, and liver disease. Moreover, sCD163 is a general risk marker of comorbidity and mortality in several chronic inflammatory disease states. Recently, sCD163 has been shown to be strongly associated with later development of type 2 diabetes in both lean and obese subjects, likely due to macrophage infiltration of adipose tissue and the liver. This review summarizes the current knowledge on the regulation of sCD163 in normal and pathological states and also deals with analytical aspects of sCD163 measurements in biological samples.

BACKGROUND: Tumor cell and host immune cell interaction plays a key role in carcinogenesis. Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer and believed to be an important mediator of tumor‐induced immunosuppression. This paper aims to describe the prognostic impact of neutrophil and dendritic cell infiltration in primary melanoma and the association of this infiltration with activated STAT3 (pSTAT3) in primary melanoma cells.METHODS: Formalin‐fixed, paraffin‐embedded primary melanomas from 186 stage‐I/II melanoma patients surgically resected from 1997 to 2000. Infiltrating neutrophils (CD66b), dendritic cells (CD123+ and DC‐LAMP+), T‐lymphocytes (CD8) and pSTAT3 melanoma cell expression were studied by immunohistochemistry and evaluated as present or absent. DC‐LAMP+ cell infiltration was evaluated as absent/few versus dense. Study endpoints: relapse‐free survival, melanoma‐specific, and overall survival.RESULTS: The median observation time was 12.2 years (range, 10.4‐14.2 years). Fifty‐one deaths were observed of which 38 (20%) were melanoma‐specific. In a multivariate Cox proportional hazards model including ulceration and melanoma thickness, neutrophil and CD123+ dendritic cell infiltration were independently associated with poor prognosis (CD66b: hazard ratio [HR] = 3.13; 95% confidence interval [CI], 1.43‐6.83; P = .004; CD123: HR = 2.45; 95% CI, 1.22‐4.92; P = .012). The association between melanoma cell pSTAT3 expression and immune infiltration (neutrophils and CD123+ cells) was strong. pSTAT3 expression, CD8 and DC‐LAMP infiltration were not independently associated with poor prognosis.CONCLUSIONS: Neutrophil infiltration and CD123+ dendritic cell infiltration in primary melanoma are independently associated with poor prognosis. Melanoma cell expression of pSTAT3 is strongly associated with the surrounding immune infiltrate. Cancer 2012;. © 2011 American Cancer Society.

Purpose: To evaluate the prognostic role of soluble CD163 (sCD163) in serum and macrophage infiltration in primary melanomas from patients with American Joint Committee on Cancer (AJCC) stage I/II melanoma. The scavenger receptor CD163 is associated with anti-inflammatory macrophages, and it is shed from their surface. Patients and Methods: Serum samples from 227 patients with stage I/II melanoma obtained before definitive surgery (baseline) and during 5 years of follow-up were analyzed for sCD163 by enzyme-linked immunosorbent assay. Excised formalin-fixed, paraffin-embedded primary melanomas from 190 patients were available for immunohistochemical analyzes of CD163⁺ and CD68⁺ macrophage infiltration. They were estimated semiquantitatively in three different tumor compartments: tumor nests, tumor stroma, and at the invasive front of the tumor. Results: Serum sCD163 treated as an updated continuous covariate as well as the baseline value were analyzed together with the covariate's ulceration and thickness in a Cox proportional hazards model. sCD163 was an independent prognostic factor for overall survival (baseline, hazard ratio [HR] = 1.4; 95% CI, 1.1 to 1.7; P = .01; and updated, HR = 1.4; 95% CI, 1.1 to 1.8; P = .003). Melanomas with dense CD163⁺ macrophage infiltration in tumor stroma and CD68⁺ macrophage infiltration at the invasive front were associated with poor overall survival (CD163, HR = 2.7; 95% CI, 0.8 to 9.3; P = .11; and CD68, HR = 2.8; 95% CI, 1.2 to 6.8; P = .02) independent (borderline for CD163) of thickness and ulceration. Conclusion: Both serum levels of sCD163 and the presence of CD68⁺ macrophage infiltration at the tumor invasive front are independent predictors of survival in AJCC stage I/II melanoma. CD163⁺ cell infiltration in tumor stroma may be predictive of survival.