Novel Function of Alternatively Activated Macrophages: Stabilin-1-Mediated Clearance of SPARC

Abstract

The matricellular protein SPARC (secreted protein acidic and rich in cysteine) has been implicated in development, differentiation, response to injury, and tumor biology by virtue of its regulation of extracellular matrix production/assembly and its antiadhesive and antiproliferative effects on different cell types. Despite numerous biological activities described for SPARC, cell surface receptors for this protein have not been identified. By phage display and in vitro-binding assays, we now show that SPARC interacts with stabilin-1, a scavenger receptor expressed by tissue macrophages and sinusoidal endothelial cells. The interaction is mediated by the extracellular epidermal growth factor-like region of stabilin-1 containing the sequence FHGTAC. Using FACS analysis and confocal microscopy, we demonstrate that stabilin-1 internalizes and targets SPARC to an endosomal pathway in Chinese hamster ovary cells stably transfected with this receptor. In human macrophages, stabilin-1 expression is required for receptor-mediated endocytosis of SPARC. SPARC was efficiently endocytosed by alternatively activated macrophages stimulated by IL-4 and dexamethasone, but not solely by Th1 or Th2 cytokines. A time course of ligand exposure to alternatively activated macrophages revealed that stabilin-1-mediated endocytosis of SPARC was followed by its targeting for degradation, similar to the targeting of acetylated low density lipoprotein, another stabilin-1 ligand. We propose that alternatively activated macrophages coordinate extracellular matrix remodeling, angiogenesis, and tumor progression via stabilin-1-mediated endocytosis of SPARC and thereby regulate its extracellular concentration.

New vistas on macrophage differentiation and activation

“…the gut macrophage) and the immunological microenvironment. Two papers published in this issue of the European Journal of Immunology [5,6], as well as other recently published reports [7][8][9][10][11], add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation.Multinucleated giant cells (MGC) are a prominent, characteristic feature of granulomas, which are caused by different agents but are exemplified by mycobacterial infections. MGC derive from the fusion of macrophages and, although different molecules have been implicated in the formation of MGC including TREM2, CD44 and more recently the P 2 X 7 nucleotide receptor [12], the molecular basis of their formation and their actual significance in chronic inflammation remains elusive.…”

“…the gut macrophage) and the immunological microenvironment. Two papers published in this issue of the European Journal of Immunology [5,6], as well as other recently published reports [7][8][9][10][11], add new elements and perspectives to the current understanding of mononuclear phagocyte differentiation and activation.…”

“…Stabilin-1 is a scavenger-like receptor expressed in alternatively activated (M2) macrophages. It has now been shown that stabilin-1 binds the matricellular protein SPARC and mediates its clearance [8], thus adding a further element linking M2 macrophages to the orchestration of extracellular matrix remodelling in normal and tumor tissues [16]. Interestingly, immature myeloid suppressor cells have functional properties and a transcriptional profile related to M2 cells [17,18].…”

“…TNF-a and GM-CSF). IL-4 and IL-13 have been found to be more than simple inhibitors of [7,8,10,11]. Intriguingly, the chemokine receptor CCR4 also plays a role in macrophage polarization, as indicated by the drift to M2 polarization observed in CCR4 -/-macrophages [13].…”

Clever‐1/Stabilin‐1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation

“…These complex mechanisms require interactions with several molecules such as intracellular sorting adaptors [13]. For example, macrophage Clever-1/Stabilin-1 mediates uptake of acetylated low-density lipoprotein [5,10] and secreted protein, acidic, rich in cysteine [14],] a regulator of tissue remodeling, cancer growth and dissemination. It is involved in intracellular sorting and lysosomal delivery of the Stabilin-1-interacting chitinase-like protein [15] and transcytosis of a GH-family hormone, placental lactogen [16].…”