Table 2.
Selection of 30 differentiating inflammation markers in untreated patients with MPS vs control subjects
| Marker | Eponym | Pathway | Function |
|---|---|---|---|
| CD5 | Pro-inflammatory | Expressed on surface of T cells | |
| CD6 | Pro-inflammatory | Expressed on surface of T cells | |
| CD8A | Pro-inflammatory | T-cell surface glycoprotein, coreceptor | |
| CD40 | Pro-inflammatory | Costimulatory protein on APCs | |
| CD244 | NK-cell receptor 2B4 | Pro-inflammatory | Cell surface receptor of NK cells (and T cells) |
| CCL4 | MIP-1β | Pro-inflammatory | Chemoattractant for NK cells and monocytes, produced by neutrophils, monocytes, T cells, B cells, fibroblasts, endothelial, and epithelial cells. Increased with age |
| CCL23 | MIP-3 | Pro-inflammatory | Chemotactic for resting T cells and monocytes |
| CXCL5 | ENA78 | Pro-inflammatory | Produced following stimulation of cells with IL-1 or TNF-α, chemotactic for neutrophils |
| CXCL 6 | GCP-2 | Pro-inflammatory | Chemoattractant for neutrophils |
| CXCL9 | MIG | Pro-inflammatory | Induces chemotaxis of CTLs, NKs, and macrophages; promotes differentiation and multiplication of leukocytes. Also causes tissue extravasation |
| IL7 | Pro-inflammatory | HGF secreted by stromal cells in BM and thymus. Also produced by keratinocytes, DCs, hepatocytes, neurons, and epithelial cells; not produced by lymphocytes. Stimulates differentiation of HSCs to myeloid progenitor cells and proliferation of all cells in lymphoid lineage (B/T/NK) | |
| IL.12B | Pro-inflammatory | Expressed by activated macrophages; acts on T and NK cells; important for sustaining sufficient number of memory/effector T helper 1 cells | |
| IL.18R1 | Pro-inflammatory | Binds IL-18; induced by IFN-α and IL-12 in NK and T cells | |
| MCP.4 | CCl13 | Pro-inflammatory | Induces chemotaxis in monocytes, eosinophils, T cells, basophils. Induced by IL-1 and TNF-α |
| VEGFA | Pro-inflammatory | Found prominently on endothelial cell membrane; also stimulates monocyte migration and increases microvascular permeability upon binding to its receptors (VEGFR1 and VEGFR2) and to heparan sulfate and heparin | |
| IL.10RB | Anti-inflammatory | Together with IL-10RA required for IL-10–induced signal transduction | |
| LAP.TGF.β.1 | Anti-inflammatory | Part of complex with latent TGF-binding protein and TGF-β. Cleaved by MMP-9 and MMP-2, TGF-β induces development of regulatory T cells, has an inhibitory effect on B-cell proliferation, stimulates resting monocytes, and inhibits activated macrophages | |
| PD.L1 | CD274 | Anti-inflammatory | Interacts with CXCL9, suppresses adaptive arm of immune system, reduces apoptosis in regulatory T cells. Expressed on T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, and vascular endothelial cells upon IFN-γ stimulation |
| RANKL | TRANCE/ TNFSF11 | Bone homeostasis | Receptor activator of NF-κB ligand. Osteoclastic activity is triggered via the osteoblasts’ surface-bound RANKL activating the osteoclasts’ surface-bound RANK |
| OPG | TNFRSF11B | Bone homeostasis | Osteoclastogenesis inhibitory factor and decoy receptor for RANKL. Also binds to TRAIL and inhibits TRAIL-induced apoptosis. GAGs also are ligands for OPG. Expressed on osteoblast lineage cells. Expression is highly regulated by estrogens. Upregulation of OPG suppresses osteoclastogenesis and bone resorption. Wnt and TGF-β are OPG-inducing cytokines |
| AXIN1 | Bone homeostasis | Negative regulator of the Wnt pathway and can induce apoptosis | |
| SCF | KIT-ligand | Growth factor/ bone homeostasis | Cytokine that binds to c-KIT receptor (CD117) and is important in the regulation of HSCs in the stem cell niche in the BM. It contributes to the self-renewal and maintenance of HSCs. Stromal cell surrounding HSCs release SCF. HSCs become less sensitive to SCF in adulthood |
| CSF.1 | Growth factor/bone homeostasis | Hematopoietic growth factor, differentiates HSCs into macrophages, drives proliferation of a pro-inflammatory macrophage phenotype in acute kidney injury. Also released by osteoblasts, binds on osteoclasts inducing differentiation | |
| DNER | Growth factor/ bone homeostasis | Δ/Notch-like epidermal growth factor-related receptor is an activator of the NOTCH1 pathway | |
| TRAIL | TNFSF10 | Apoptosis/bone homeostasis | Produced by most normal tissue cells and induces caspase-8–dependent apoptosis after binding to death receptors DR4 and DR5. Also ligand for DcDR1 (TRAIL-neutralizing decoy-receptor), DcDR2 (activates NF-κB pathway), and OPG. TRAIL induces osteoclastogenesis by binding to specific TRAIL receptors on osteoclast precursor cell surfaces |
| TWEAK | TNFSF12 | Apoptosis | Ligand for TWEAKR receptor and can induce apoptosis via multiple pathways. Produced mainly by leukocytes, including monocytes, DCs, and NK cells |
| MMP.1 | ECM degradation | MMP enzyme in ECM remodeling; targets collagen types I, II, and III. HGF activates MMP-1 activity via the Etsy transcription family | |
| MMP.10 | ECM degradation | MMP enzyme in ECM remodeling, targets among others proteoglycans, cleaves precursor of MMP.1 | |
| uPA | ECM degradation | uPA, primary substrate is plasminogen (precursor of plasmin). Activation of plasmin can trigger a proteolytic cascade that participates in thrombolysis or extracellular matrix degradation. uPA also can cleave pro-HGF. Ligand for uPAR, expressed by both osteoblasts and osteoclasts | |
| HGF | SF | ECM degradation/ growth factor | Paracrine cellular growth, motility, and morphogenic factor secreted by mesenchymal cells as pro-HGF which is among others activated by uPA. Primarily targets epithelial and endothelial cells but also hemopoietic progenitor cells and T cells. HGF upregulates the expression of IL-11 from osteoclast-like cells and inhibits osteoblast differentiation. HGF increases production of MMP-1 and uPA. Has an antifibrotic effect in various organs |
Markers that were present in both the list of markers that were significantly different and had a log2 fold change >1.5 in the supervised analysis and the top 40 markers within the first principal component of PCA. Markers are categorized based on their relation to MPS pathology. APCs, antigen presenting cells; AXIN1, axis inhibition protein 1; BM, bone marrow; CCL, C-C motif chemokine ligand; CD, cluster of differentiation; CSF, colony-stimulating factor; CTLs, cytotoxic T lymphocytes; CXCL, C-C-C motif chemokine ligand; DcDR, decoy death receptor; DCs, dendritic cells; DNER, delta/notch-like epidermal growth factor-related receptor; DR, death receptor; ECM, extracellular matrix; ENA, epithelial-derived neutrophil-activating peptide; GAG, glycosaminoglycan; GCP-2, granulocyte chemotactic protein 2; HGF, hepatocyte growth factor; HSCs, hematopoietic stem cells; IFN, interferon; IL-1, interleukin 1; LAP.TGF.b.1, latency-associated peptide and transforming growth factor beta-1; MCP, monocyte chemoattractant protein; MIG, monokine induced by gamma interferon; MIP, macrophage inflammatory protein; MMP-9, matrix metalloproteinase-9; NK cell, natural killer cell; OPG, osteoprotegerin; PD.L1, programmed death ligand 1; RANK, receptor activator of nuclear factor kappa-B; RANKL, receptor activator of nuclear factor kappa-B ligand; SCF, stem cell factor; SF, scatter factor; TGF-β, transforming growth factor β; TNFSF, tumor necrosis factor superfamily; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; TRANCE, TNF-related activation-induced cytokine; TWEAK, tumor necrosis factor weak inducer of apoptosis; TWEAKR, tumor necrosis factor weak inducer of apoptosis receptor; uPA urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor. VEGFA, vascular endothelial growth factor AVEGFR, vascular endothelial growth factor receptor.