Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway

Abstract

IntroductionMacrophages are essential elements of innate immunity that orchestrate inflammatory reactions and immune tolerance as well as healing processes and tissue homeostasis. Macrophages perform these functions by the tightly regulated production of cytokines, enzymes, extracellular matrix (ECM) components, and other mediators. Alternatively, macrophages may also bind and internalize these molecules, thereby contributing to their inactivation and degradation. The high specificity and flexibility of this clearance function are based on the expression of multiple endocytic receptors by macrophages. 1 The molecular patterns of macrophage secretory and clearance functions are regulated by the activation status and the polarization of the macrophages involved. [2][3][4] Besides the classic, constitutively operating ER/Golgi secretory pathway, which is regulated primarily on the level of gene expression, macrophages use nonclassic 5 and lysosomal secretory pathways. [6][7][8] The lysosomal secretion route is regulated by specific sorting of newly synthesized products into secretory lysosomes and by stimulus-dependent vesicular/membrane biogenesis. 9 Constitutive sorting of soluble cargo proteins from the Golgi to the endosomal/ lysosomal system is mediated by mannose 6-phosphate receptors CD-MPR and CI-MPR, 2 major sorting receptors in numerous cell types. 10,11 Cell-type-specific mechanisms for the selective delivery of cargo proteins to lysosomes, however, have hitherto remained elusive. Recently, we have presented evidence for the hypothesis that Th2-polarized macrophages use specific, stimulus-dependent mechanisms for protein delivery from the Golgi compartments to the endosomal/lysosomal system, where the selection of the cargo is mediated by stabilin-1. 12 Stabilin-1 is a type 1 transmembrane receptor previously identified by us that shows a unique cell and tissue distribution. 13,14 Stabilin-1 is a marker for alternative macrophage activation 2 ; it is expressed by specialized tissue macrophages in placenta, skin, gut, and pancreas; in cardiac and skeletal muscle; and by sinusoidal endothelial cells in liver, spleen, bone marrow, and lymph nodes. 2,15 In vitro, the expression of stabilin-1 can be induced in monocytederived macrophages by stimulation with interleukin-4 (IL-4) and dexamethasone, but not interferon ␥ (IFN␥). Stabilin-1 functions as an endocytic receptor in endothelial cells and macrophages; its ligand repertoire, however, differs from that of its closest homolog, stabilin-2. 12,16 While stabilin-2 has been shown to be a specialized scavenger receptor of sinusoidal endothelial cells mediating uptake of hyaluronic acid, AGE, and procollagen peptides, the only well-established ligand for stabilin-1 to date is acLDL. 17,18 In addition to endocytosis/recycling, stabilin-1 is involved in trafficking between early/sorting endosomes and the trans-Golgi network 12 in human macrophages. Shuttling of stabilin-1 between For personal use only. on March 26, 2019. by guest www.bloodjournal.org From the bios...

YKL-40/CHI3L1 drives inflammation on the road of tumor progression

“…Stimulation with various cytokines, including IL-13, IL-6, TNF-a, and IL-1b, induces the production of YKL-40/CHI3L1. In human macrophages, YKL-40/CHI3L1 is stimulated by a key TH1 cytokine, IFN-g, but is suppressed by the TH2 cytokine, IL-4 [10]. Interestingly, our studies have shown that YKL-40/CHI3L1 downregulates the production of IFN-g in T lymphocytes [11].…”

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

“…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].It is currently unknown whether Clever-1/Stabilin-1 is involved in lymphocyte migration via afferent lymphatics into the draining lymph nodes and whether it can be used as a target for anti-inflammatory therapy. Therefore, this work was designed to elucidate the role of Clever-1/Stabilin-1 in lymphocyte trafficking and to study the therapeutic efficacy of anti-Clever-1/Stabilin-1 Ab in inflammation.…”

“…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].…”

Chitinase 3-like-1 enhances bacterial adhesion to colonic epithelial cells through the interaction with bacterial chitin-binding protein

“…The members of mammalian chitinases and chitinase-like proteins include chitinase 3-like-1 (CHI3L1; also known as YKL-40 or human cartilage glycoprotein 39 (HCgp-39)), 3 chitotriosidase, 4 YKL-39, 5 Ym1, 6 acidic mammalian chitinase (AMCase), 7 oviduct-specific glycoprotein 8 and stabilin-1-interacting chitinase-like protein. 9 Chitinase 3-like-1 is a 40-kDa mammalian glycoprotein 8,10,11 and is produced by human synovial cells, 12 osteosarcoma cells, 10 chondrocytes, 3,13 smooth muscle cells, 14 macrophages, 15,16 neutrophils, 17 colonic epithelial cells (CECs) 18 and others. AMCase and chitotriosidase have catalytic activity, but the other chitinases including CHI3L1 do not possess the enzymatic activity.…”