Melanocortin Receptor Mediated Anti-inflammatory Effect of Repository Corticotropin Injection on Human Monocyte-derived Macrophages
ECTRIMS Online Library. Healy L. 10/25/17; 199501; EP1481
Luke M. Healy
Luke M. Healy
Contributions
Abstract

Abstract: EP1481

Type: ePoster

Abstract Category: Pathology and pathogenesis of MS - 15 Immunology

Introduction: Repository corticotropin injection ((RCI), H.P. Acthar Gel®) contains a purified porcine pituitary ACTH-analogue and is FDA-approved to treat acute multiple sclerosis (MS) exacerbations. ACTH may have activity at all five melanocortin receptor (MCR) subtypes that are differentially expressed on multiple immune and non-immune cell populations. MRC agonists are reported to inhibit pro-inflammatory responses in blood-derived macrophages. Monocyte-derived-macrophages (MDMs) are the dominant cell type in an MS lesion and play a pivotal role in regulating the immune response and development of plaques in MS.
Objective: To explore the direct effects of RCI on human macrophages in vitro, focusing on induction of pro-inflammatory mediators following lipopolysaccharide (LPS) stimulation.
Methods: Human blood derived monocytes were selected for CD14 expression using magnetic bead selection (MACs) and plated in presence of macrophage colony-stimulating factor (M-CSF). Cells were stimulated with LPS and incubated for a minimum for 24h with and without RCI preparations (3h pre-treatment). Assays: qPCR assays were performed using Taqman platform. ELISA reagents for various cytokines were sourced from BD Biosciences. Receptor expression data was mined from microarray and RNAseq datasets.
Results: MDMs express MC1R exclusively as shown by transcriptomic and PCR analysis. Expression of MC1R was reduced by LPS stimulation and this was not affected by RCI application. Treatment of MDMs with RCI suppressed LPS-induced production of TNF and IL6 (range, 75-80%). Furthermore, RCI treatment of MDMs induced expression of heme oxygenase-1 (HMOX1), a gene that is upregulated during periods of metabolic stress.
Conclusion: Our in vitro study showing that RCI directly inhibits the pro-inflammatory response of human MDMs indicates that this agent can induce an anti-inflammatory effect independent of the corticosteroid pathway. Whether this anti-inflammatory effect on MDMs can impact other functional roles such as phagocytosis, tissue repair or promoting remyelination remains to be established.
Disclosure:
Luke M. Healy: nothing to disclose.
Yun Hsuan Lin: nothing to disclose.
Jeong Ho Jang: nothing to disclose.
Vijayaraghava Rao: nothing to disclose.
Dale Wright is a full-time employee of Mallinckrodt ARD Inc.
Funding: This work was funded through a grant to McGill University from Mallinckrodt ARD Inc

Abstract: EP1481

Type: ePoster

Abstract Category: Pathology and pathogenesis of MS - 15 Immunology

Introduction: Repository corticotropin injection ((RCI), H.P. Acthar Gel®) contains a purified porcine pituitary ACTH-analogue and is FDA-approved to treat acute multiple sclerosis (MS) exacerbations. ACTH may have activity at all five melanocortin receptor (MCR) subtypes that are differentially expressed on multiple immune and non-immune cell populations. MRC agonists are reported to inhibit pro-inflammatory responses in blood-derived macrophages. Monocyte-derived-macrophages (MDMs) are the dominant cell type in an MS lesion and play a pivotal role in regulating the immune response and development of plaques in MS.
Objective: To explore the direct effects of RCI on human macrophages in vitro, focusing on induction of pro-inflammatory mediators following lipopolysaccharide (LPS) stimulation.
Methods: Human blood derived monocytes were selected for CD14 expression using magnetic bead selection (MACs) and plated in presence of macrophage colony-stimulating factor (M-CSF). Cells were stimulated with LPS and incubated for a minimum for 24h with and without RCI preparations (3h pre-treatment). Assays: qPCR assays were performed using Taqman platform. ELISA reagents for various cytokines were sourced from BD Biosciences. Receptor expression data was mined from microarray and RNAseq datasets.
Results: MDMs express MC1R exclusively as shown by transcriptomic and PCR analysis. Expression of MC1R was reduced by LPS stimulation and this was not affected by RCI application. Treatment of MDMs with RCI suppressed LPS-induced production of TNF and IL6 (range, 75-80%). Furthermore, RCI treatment of MDMs induced expression of heme oxygenase-1 (HMOX1), a gene that is upregulated during periods of metabolic stress.
Conclusion: Our in vitro study showing that RCI directly inhibits the pro-inflammatory response of human MDMs indicates that this agent can induce an anti-inflammatory effect independent of the corticosteroid pathway. Whether this anti-inflammatory effect on MDMs can impact other functional roles such as phagocytosis, tissue repair or promoting remyelination remains to be established.
Disclosure:
Luke M. Healy: nothing to disclose.
Yun Hsuan Lin: nothing to disclose.
Jeong Ho Jang: nothing to disclose.
Vijayaraghava Rao: nothing to disclose.
Dale Wright is a full-time employee of Mallinckrodt ARD Inc.
Funding: This work was funded through a grant to McGill University from Mallinckrodt ARD Inc

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