Melanocortin Control of Cell Trafficking in Vascular Inflammation

Patel, Hetal; Leoni, Giovanna; Montero‐Melendez, Trinidad; Sampaio, André Luiz Franco; Perretti, Mauro

doi:10.1007/978-1-4419-6354-3_7

Cited by 16 publications

(16 citation statements)

References 85 publications

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“…What does remain in its infancy is the pattern in which MCs may be expressed in specific disease, nevertheless this area of research and drug development has become particularly eye-catching as seen with the development of AP214 for the treatment of post-surgical kidney injury following cardiac heart surgery in phase II trials (). Other melanocortin-based therapies are in the development pipeline for biotechnology companies with emphasis on obesity and sexual dysfunction as disease targets (Patel et al, 2010b). …”

Section: Resultsmentioning

confidence: 99%

Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

et al. 2011

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Macrophages have crucial functions in initiating the inflammatory reaction in a strict temporal and spatial manner to provide a “clear-up” response required for resolution. Hormonal peptides such as melanocortins modulate macrophage reactivity and attenuate inflammation ranging from skin inflammation to joint disease and reperfusion injury. The melanocortins (e.g., adrenocorticotrophin, ACTH and αMSH) elicit regulatory properties through activation of a family of GPCRs, the melanocortin (MC) receptors; MC1–MC5. Several studies have focused on MC1 and MC3 as anti-inflammatory receptors expressed on cells of the macrophage lineage. We review here elements of the melanocortin pathway with particular attention to macrophage function in anti-inflammatory and pro-resolving inflammatory settings. Evidence shows that ACTH, αMSH, and other MC agonists can activate MC1 and MC3 on macrophage through cAMP and/or NFκB-dependent mechanisms to abrogate pro-inflammatory cytokines, chemokines, and NO and enhance anti-inflammatory mediators such as IL-10 and HO-1. Melanocortins and their receptors regulate inflammation by inhibiting leukocyte recruitment to and interaction with inflamed tissue. An intensely exciting addition to this field of research has been the ability of an αMSH analog; AP214 to activate MC3 expressed on macrophage to enhance their clearance of both zymosan particles and apoptotic neutrophils thus putting melanocortins in line with other pro-resolving mediators. The use of mouse colonies mutated or nullified for MC1 or MC3, respectively as well as availability of selective MC receptor agonist/antagonists have been key to deciphering mechanisms by which elements of the melanocortin system play a role in these phenomena. We review here melanocortin pathway components with attention to the macrophage, reiterating receptor targets required for pro-resolving properties. The overall outcome will be identification of selective MC agonists as a strategy for innovative anti-inflammatory therapeutics.

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Section: Resultsmentioning

confidence: 99%

Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

et al. 2011

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“…This area of investigation encompasses anti-inflammatory effects in the brain, gouty arthritis and during reperfusion injury (Catania 2007; Catania, et al 2010; Gatti, et al 2010; Getting, et al 2001; Holloway, et al 2011; Leoni, et al 2010; Montero-Melendez, et al 2011; Muceniece and Dambrova 2010; Patel, et al 2010). Leukocytes produce POMC and melanocortin peptides, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Leukocytes produce POMC and melanocortin peptides, i.e. ACTH and α-MSH, in response to inflammatory mediators which then act in an autocrine fashion to reduce inflammatory cytokine production and leukocyte trafficking during inflammation (Catania 2007; Getting et al 2001; Leoni et al 2010; Patel et al 2010). The MC1-R, MC3-R and MC5-R have been implicated as the mediators of these actions in immune cells.…”

Section: Introductionmentioning

confidence: 99%

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Evans

Fernando

Ragolia

2012

Molecular and Cellular Endocrinology

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A local melanocortin system is active during tissue injury and inflammation. Thus far this system has been described as autocrine in nature where local production of pro-opiomelanocortin (POMC) peptides by leukocytes feeds back on melanocortin receptor (MC-R) expressing immune cells to quell inflammatory cytokine production. Here we present evidence that POMC peptides may generate extracellular matrix (ECM) changes by inducing matrix production by cells of the mesenchymal lineage through activation of the MC2-R. Using immunoblot, we determined that mouse aorta-derived mesenchymal progenitor cells express both MC2-R and MC3-R. These progenitors respond to treatment with ACTH by increasing collagen matrix synthesis as assessed by picrosirius red stain and 3H-proline incorporation. ACTH also induces transient increases in intracellular calcium ([Ca2+]i) as assessed using the fluorescent Ca2+ indicator, fura- 2. The ACTH-induced changes in [Ca2+]i are consistent with MC2-R signaling and consist of both an intracellular release and an extracellular influx of Ca2+. Both mouse aortic mesenchymal progenitors and mouse macrophage cells express POMC and the prohormone convertase 1/3 (PC1/3) indicating they have the potential to contribute to the local production of POMC peptides. These data demonstrate functional MC2-R expression in mouse aorta-derived mesenchymal progenitors and implicate both macrophage and mesenchymal cells as relevant sources of local POMC peptides.

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“…This area of investigation encompasses anti-inflammatory effects in the brain, gouty arthritis and during reperfusion injury [4, 5, 21, 22, 25, 34, 36, 37, 41]. The MC1-R, MC3-R and MC5-R have been implicated as the mediators of these actions in immune cells.…”

Section: Pomc Peptides and Mc-r; Expression In Immune Cells And Rolesmentioning

confidence: 99%

“…In response to inflammatory mediators, leukocytes produce melanocortin peptides, i.e. ACTH and α-MSH, which then act in an autocrine fashion to reduce inflammatory cytokine production and leukocyte trafficking during inflammation [4, 22, 34, 41]. Therefore a damaged hypertensive vasculature in diabetes and obesity is not only exposed to systemic elevations in ACTH and glucocorticoid, but local elevations of ACTH via production by leukocytes.…”

Section: Pomc Peptides and Mc-r; Expression In Immune Cells And Rolesmentioning

confidence: 99%

Systemic and local ACTH produced during inflammatory states promotes osteochondrogenic mesenchymal cell differentiation contributing to the pathologic progression of calcified atherosclerosis

Evans

Ragolia

2012

Medical Hypotheses

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There are many well-known roles for the proopiomelanocortin (POMC) derived peptides and their receptors, the melanocortin receptors (MC-R). The focus here is on the evolving role of the melanocortin system in inflammation. Chronic inflammatory states such as those occurring in diabetes and obesity are associated with both a hyperactive hypothalamic-pituitary-adrenal (HPA) axis as well as increased incidence of atherosclerosis. An inflammation-induced hyperactive HPA axis along with increased leukocyte infiltration can lead to significant exposure to melanocortin peptides, particularly ACTH, in an inflamed vasculature. Mesenchymal progenitor cells are present throughout the vasculature, express receptors for the melanocortin peptides, and respond to ACTH with increased osteochondrogenic differentiation. Coupled to the increased exposure to ACTH during HPA hyperactivity is increased glucocorticoid (GC) exposure. GCs also promote chondrogenic differentiation of mesenchymal progenitors and increase their expression of MC-R as well as their expression of POMC and its cleavage products. It is hypothesized that during inflammatory states systemically produced ACTH and glucocorticoid as well as ACTH produced locally by macrophage and other immune cells, can influence and potentiate mesenchymal progenitor cell differentiation along the osteochondrogenic lineages. In turn the increase in osteochondrogenic matrix contributes to the pathophysiological progression of the calcified atherosclerotic plaque. The roles of the melanocortin system in inflammation and its resolution have just begun to be explored. Investigations into the ACTH-induced matrix changes among mesenchymal cell populations are warranted. ACTH signaling through the MC-R represents a new therapeutic target for the prevention and treatment of calcified atherosclerosis.

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Melanocortin Control of Cell Trafficking in Vascular Inflammation

Cited by 16 publications

References 85 publications

Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

Functional melanocortin-2 receptors are expressed by mouse aorta-derived mesenchymal progenitor cells

Systemic and local ACTH produced during inflammatory states promotes osteochondrogenic mesenchymal cell differentiation contributing to the pathologic progression of calcified atherosclerosis

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