Tumor necrosis factor α-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163

Abstract

CD163 is expressed specifically in the monocyte/macrophage lineage, where it mediates uptake of haptoglobin-hemoglobin complexes, leading to metabolism of the oxidative heme molecule. Shedding of the CD163 ectodomain from the cell surface produces a sCD163 plasma protein, and a positive correlation is seen between the sCD163 plasma level and the severity of various infectious and inflammatory diseases. In the present analysis of the phorbol ester-induced shedding of sCD163 in CD163 cDNA-transfected HEK293 cells, we used metalloproteinase inhibitors and siRNA-mediated inhibition of metalloproteinases to identify TACE/ADAM17 as an enzyme responsible for PMA-induced cleavage of the membrane-proximal region of CD163. As TACE/ADAM17-mediated shedding of TNF-α is up-regulated in macrophages subjected to inflammatory stimuli, the present results now provide a likely explanation for the strong empirical relationship between the sCD163 plasma level and infectious/inflammatory diseases relating to macrophage activity.

Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema

“…An increase in circulating sCD163 has been previously described in many acute inflammatory conditions, including sepsis and acute coronary syndrome 19, 20. Ectodomain shedding of soluble CD163 from the cell surface of monocytic cells is believed to be the direct result of upregulated CD163 and TNF‐ α expression by macrophages 21. While TNF‐ α is fairly rapidly cleared, soluble CD163 may be a long‐lived surrogate marker for macrophage activation following tissue injury 16.…”

Soluble CD163: a biomarker linking macrophages and insulin resistance

“…In this study, sCD163 was a strong independent predictor of HOMA-IR, whereas TNF-α and IL-6 were not. This is interesting, since sCD163 and TNF-α share similar mechanisms of shedding by TACE from activated macrophages [9]. However, sCD163 may predict insulin resistance better due to the almost complete monocyte-macrophage specificity of CD163 and the longer plasma half-life of sCD163 (t ½ 0approximately 1 day) [9], which makes it a more robust biomarker than TNF-α (t ½ 018 min) [26].…”

“…TNF-α is cleaved into a soluble form and released from the cell surface by proteolytic action of the metalloproteinase TNF-α-converting enzyme (TACE/ADAM17) [8]. Recently it has been shown that TACE is also responsible for the shedding of macrophagespecific soluble CD163 (sCD163) [9]. Plasma sCD163 is regarded as a longer duration circulating marker of TNF-α, and concentrations of sCD163 are increased in obese [10,11] and type 2 diabetic patients [12], consistent with macrophage accumulation in the adipose tissue.…”

CD163, a Hemoglobin/Haptoglobin Scavenger Receptor, After Intracerebral Hemorrhage: Functions in Microglia/Macrophages Versus Neurons

“…The ectodomain of CD163 can be shed from the cell surface by the protease ADAM17 (a disintegrin and metalloproteinase domain-17) [26]. This shedding occurs near a palindromic RSSR amino acid sequence near the outer membrane of the cell [27].…”