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Folate receptor-? constitutes a marker for human proinflammatory monocytes.

ABSTRACT: Activated macrophages are commonly involved in the pathogenesis of inflammatory and autoimmune diseases and have been frequently reported to overexpress FR-?. Although FR-targeted therapies aimed at eliminating activated macrophages have shown promise for treating inflammatory diseases, little work has been performed to evaluate whether other hematopoietic cells might also express FR-?. Analysis of peripheral blood cells with a mAb to human FR-? reveals that only monocytes express FR-?. Molecular characterization of these circulating monocytes further demonstrates that solely the classic/proinflammatory subset (CD14(high)CD16(-)) expresses the FR and that only CD14(high)CD16(-) FR-?(+) monocytes also display the ability to bind folate-linked molecules. Confirmation that this subset of monocytes indeed constitutes the proinflammatory subpopulation was obtained by demonstrating coexpression of FR-? with other proinflammatory markers, including CCR2 and HLA-DR. Synovial monocytes from the joints of patients with RA were also shown to express FR-?. As inhibition of the chemotaxis of proinflammatory monocytes into sites of inflammation has been explored frequently as a means of controlling autoimmune diseases, demonstration that FR-? is uniquely expressed on this proinflammatory subpopulation offers a new strategy to suppress migration of inflammatory monocytes into sites of inflammation.

SUBMITTER: Shen J

PROVIDER: S-EPMC4163630 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Folate receptor-β constitutes a marker for human proinflammatory monocytes.

Shen Jiayin J Hilgenbrink Andrew R AR Xia Wei W Feng Yang Y Dimitrov Dimiter S DS Lockwood Michael B MB Amato Robert J RJ Low Philip S PS

Journal of leukocyte biology 20140711 4

Activated macrophages are commonly involved in the pathogenesis of inflammatory and autoimmune diseases and have been frequently reported to overexpress FR-β. Although FR-targeted therapies aimed at eliminating activated macrophages have shown promise for treating inflammatory diseases, little work has been performed to evaluate whether other hematopoietic cells might also express FR-β. Analysis of peripheral blood cells with a mAb to human FR-β reveals that only monocytes express FR-β. Molecula ...[more]

PMID: 25015955

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Project description:Summary Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development. Graphical abstract Highlights • Functional folate receptor beta is transiently expressed on inflammatory monocytes• EC2319 is an enhancement of traditional dihydrofolate reductase inhibitors• EC2319 anti-monocyte activity correlates with local/systemic therapeutic benefit• EC2319 inhibition of cytokine release suggests emergency use for hyperinflammation By repurposing the antifolate aminopterin, Lu et al. reveal a rationally designed single-agent therapy that effectively mitigates monocyte/macrophage dysfunction. The observed biological effect appears to be independent of root causes of acute inflammation, which is frequently associated with autoimmune and inflammatory diseases, viral or bacterial infections, and cytokine storm disorders.

Project description:Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi's sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. KSHV establishes lytic infection of monocytes in vivo, which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1?, 1?, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression.IMPORTANCE KSHV is the etiologic agent of Kaposi's sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1?, 1?, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease.

Project description:The reactions of carbohydrate- or lipid-derived intermediates with proteins lead to the formation of Maillard reaction products, which subsequently leads to the formation of advanced glycation/lipoxidation end products (AGE/ALEs). Levels of AGE/ALEs are increased in diseases like diabetes. Unlike AGEs, very little is known about ALE effects in vitro. We hypothesized that ALEs can have proinflammatory effects in monocytes.In a profiling approach, conditioned media from THP-1 cells either cultured in normal glucose (5.5 mmol/l) or treated with MDA-Lys or MDA alone were hybridized to arrays containing antibodies to 120 known human cytokines/chemokines. Pathway analyses with bioinformatics software were used to identify signalling networks.Synthetic ALE (malondialdehyde-lysine [MDA-Lys]) (50 micromol/l) could induce oxidant stress and also activate the transcriptional factor nuclear factor-kappaB (NF-kappaB) in THP-1 monocytes. MDA-Lys also significantly increased the expression of key candidate proinflammatory genes, interferon-gamma-inducible protein-10, beta1- and beta2-integrins, cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 and -8, and inducible nitric-oxide synthase, which are also associated with monocyte dysfunction. Several key target proinflammatory proteins were significantly induced by MDA-Lys relative to normal glucose or MDA alone, including MCP-1; tumor necrosis factor ligand superfamily member-14; chemokine CC motif ligand-11 (CCL11); growth-related oncogene-alpha, -beta, and -gamma; and chemokine CXC motif ligand-13. Bioinformatics analyses identified a network of chemokine signaling among MDA-Lys-regulated genes. MDA-Lys also increased monocyte binding to vascular smooth muscle and endothelial cells. Furthermore, plasma from diabetic rats showed significantly higher levels of MDA-Lys and CCL11.These new results suggest that ALEs can promote monocyte activation and vascular complications via induction of inflammatory pathways and networks.

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Folate receptor-? constitutes a marker for human proinflammatory monocytes.

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Folate receptor-β constitutes a marker for human proinflammatory monocytes.

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