Publications by authors named "Trinidad Montero-Melendez"

31 Publications

Loss of 15-lipoxygenase disrupts T differentiation altering their pro-resolving functions.

Cell Death Differ 2021 May 27. Epub 2021 May 27.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK.

Regulatory T-cells (T) are central in the maintenance of homeostasis and resolution of inflammation. However, the mechanisms that govern their differentiation and function are not completely understood. Herein, we demonstrate a central role for the lipid mediator biosynthetic enzyme 15-lipoxygenase (ALOX15) in regulating key aspects of T biology. Pharmacological inhibition or genetic deletion of ALOX15 in T decreased FOXP3 expression, altered T transcriptional profile and shifted their metabolism. This was linked with an impaired ability of Alox15-deficient cells to exert their pro-resolving actions, including a decrease in their ability to upregulate macrophage efferocytosis and a downregulation of interferon gamma expression in Th1 cells. Incubation of T with the ALOX15-derived specilized pro-resolving mediators (SPM)s Resolvin (Rv)D3 and RvD5 rescued FOXP3 expression in cells where ALOX15 activity was inhibited. In vivo, deletion of Alox15 led to increased vascular lipid load and expansion of Th1 cells in mice fed western diet, a phenomenon that was reversed when Alox15-deficient mice were reconstituted with wild type T. Taken together these findings demonstrate a central role of pro-resolving lipid mediators in governing the differentiation of naive T-cells to T.
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http://dx.doi.org/10.1038/s41418-021-00807-xDOI Listing
May 2021

Extracellular vesicles from monocyte/platelet aggregates modulate human atherosclerotic plaque reactivity.

J Extracell Vesicles 2021 Apr 27;10(6):12084. Epub 2021 Apr 27.

William Harvey Research Institute Bart's and the London School of Medicine Queen Mary University of London London UK.

Extracellular vesicles (EVs) are emerging as key players in different stages of atherosclerosis. Here we provide evidence that EVs released by mixed aggregates of monocytes and platelets in response to TNF-α display pro-inflammatory actions on endothelial cells and atherosclerotic plaques. Tempering platelet activation with Iloprost, Aspirin or a P2Y inhibitor impacted quantity and phenotype of EV produced. Proteomics of EVs from cells activated with TNF-α alone or in the presence of Iloprost revealed a distinct composition, with interesting hits like annexin-A1 and gelsolin. When added to human atherosclerotic plaque explants, EVs from TNF-α stimulated monocytes augmented release of cytokines. In contrast, EVs generated by TNF-α together with Iloprost produced minimal plaque activation. Notably, patients with coronary artery disease that required percutaneous coronary intervention had elevated plasma numbers of monocyte, platelet as well as double positive EV subsets. In conclusion, EVs released following monocyte/platelet activation may play a potential role in the development and progression of atherosclerosis. Whereas attenuating platelet activation modifies EV composition released from monocyte/platelet aggregates, curbing their pro-inflammatory actions may offer therapeutic avenues for the treatment of atherosclerosis.
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http://dx.doi.org/10.1002/jev2.12084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077084PMC
April 2021

Senescence under appraisal: hopes and challenges revisited.

Cell Mol Life Sci 2021 Apr 13;78(7):3333-3354. Epub 2021 Jan 13.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

In recent years, cellular senescence has become the focus of attention in multiple areas of biomedical research. Typically defined as an irreversible cell cycle arrest accompanied by increased cellular growth, metabolic activity and by a characteristic messaging secretome, cellular senescence can impact on multiple physiological and pathological processes such as wound healing, fibrosis, cancer and ageing. These unjustly called 'zombie cells' are indeed a rich source of opportunities for innovative therapeutic development. In this review, we collate the current understanding of the process of cellular senescence and its two-faced nature, i.e. beneficial/detrimental, and reason this duality is linked to contextual aspects. We propose the senescence programme as an endogenous pro-resolving mechanism that may lead to sustained inflammation and damage when dysregulated or when senescent cells are not cleared efficiently. This pro-resolving model reconciles the paradoxical two faces of senescence by emphasising that it is the unsuccessful completion of the programme, and not senescence itself, what leads to pathology. Thus, pro-senescence therapies under the right context, may favour inflammation resolution. We also review the evidence for the multiple therapeutic approaches under development based on senescence, including its induction, prevention, clearance and the use of senolytic and senomorphic drugs. In particular, we highlight the importance of the immune system in the favourable outcome of senescence and the implications of an inefficient immune surveillance in completion of the senescent cycle. Finally, we identify and discuss a number of challenges and existing gaps to encourage and stimulate further research in this exciting and unravelled field, with the hope of promoting and accelerating the clinical success of senescence-based therapies.
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http://dx.doi.org/10.1007/s00018-020-03746-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038995PMC
April 2021

Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis.

Nat Commun 2020 02 6;11(1):745. Epub 2020 Feb 6.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.
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http://dx.doi.org/10.1038/s41467-020-14421-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005314PMC
February 2020

Ligand Bias and Its Association With Pro-resolving Actions of Melanocortin Drugs.

Front Pharmacol 2018 14;9:919. Epub 2018 Aug 14.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.

Resolution Pharmacology identifies drugs developed on the biology of the resolution phase of inflammation, the complex molecular and cellular network of events that ensure the tight temporal and spatial control on the inflammatory response. As such, new anti-inflammatory and pro-resolving drugs could derive from pro-resolving mediators and receptors. To implement faithful screening programs, however, it is important to rely on predictive signaling pathway relevant for the ultimate bio-action of interest. Herein we performed an analysis with four prototypical melanocortin receptor (MC) agonists. The choice fell on the natural agonist αMSH, the small molecule BMS-470539, and the synthetic derivatives [D-Trp]-γMSH and [Nle,D-Phe]-αMSH. We used human macrophages and quantified the effect of the four agonists on inhibition of cytokine release and promotion of efferocytosis. All agonists (1-10 μM) significantly inhibited cytokine release by LPS-stimulated cells whereas [D-Trp]-γMSH was the most effective in inducing efferocytosis (∼60% increase). To study the signaling profile, we monitored cAMP accumulation and ERK1/2 phosphorylation, and constructed biased plots that revealed a marked biased profile of [D-Trp]-γMSH toward phospho-ERK1/2. Correlation matrix analysis of all data pointed at phospho-ERK1/2 at any receptor as the most prominent pathway to attain pro-phagocytic actions, and MC receptor as the most relevant to drive anti-cytokine effects. In conclusion, the present study highlights the need to associate single-target signaling data with relevant functional outcomes. In this manner, we would increase our chances to optimize drug discovery programs during the early target validation and hit-to-lead phases.
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http://dx.doi.org/10.3389/fphar.2018.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102781PMC
August 2018

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates.

J Immunol 2017 04 27;198(7):2876-2885. Epub 2017 Feb 27.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, United Kingdom; and

We hypothesized that exudates collected at the beginning of the resolution phase of inflammation might be enriched for tissue protective molecules; thus an integrated cellular and molecular approach was applied to identify novel chondroprotective bioactions. Exudates were collected 6 h (inflammatory) and 24 h (resolving) following carrageenan-induced pleurisy in rats. The resolving exudate was subjected to gel filtration chromatography followed by proteomics, identifying 61 proteins. Fractions were added to C28/I2 chondrocytes, grown in micromasses, ions with or without IL-1β or osteoarthritic synovial fluids for 48 h. Three proteins were selected from the proteomic analysis, α1-antitrypsin (AAT), hemopexin (HX), and gelsolin (GSN), and tested against catabolic stimulation for their effects on glycosaminoglycan deposition as assessed by Alcian blue staining, and gene expression of key anabolic proteins by real-time PCR. In an in vivo model of inflammatory arthritis, cartilage integrity was determined histologically 48 h after intra-articular injection of AAT or GSN. The resolving exudate displayed protective activities on chondrocytes, using multiple readouts: these effects were retained in low m.w. fractions of the exudate (46.7% increase in glycosaminoglycan deposition; ∼20% upregulation of COL2A1 and aggrecan mRNA expression), which reversed the effect of IL-1β. Exogenous administration of HX, GSN, or AAT abrogated the effects of IL-1β and osteoarthritic synovial fluids on anabolic gene expression and increased glycosaminoglycan deposition. Intra-articular injection of AAT or GSN protected cartilage integrity in mice with inflammatory arthritis. In summary, the strategy for identification of novel chondroprotective activities in resolving exudates identified HX, GSN and AAT as potential leads for new drug discovery programs.
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http://dx.doi.org/10.4049/jimmunol.1601111DOI Listing
April 2017

Old drugs with new skills: fenoprofen as an allosteric enhancer at melanocortin receptor 3.

Cell Mol Life Sci 2017 04 16;74(7):1335-1345. Epub 2016 Nov 16.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

The efficiency of drug research and development has paradoxically declined over the last decades despite major scientific and technological advances, promoting new cost-effective strategies such as drug repositioning by systematic screening for new actions of known drugs. Here, we performed a screening for positive allosteric modulators (PAMs) at melanocortin (MC) receptors. The non-steroidal anti-inflammatory drug fenoprofen, but not the similar compound ibuprofen, presented PAM activity at MC, MC, and MC receptors. In a model of inflammatory arthritis, fenoprofen afforded potent inhibition while ibuprofen was nearly inactive. Fenoprofen presented anti-arthritic actions on cartilage integrity and synovitis, effects markedly attenuated in Mc3r-/- mice. Fenoprofen displayed pro-resolving properties promoting macrophage phagocytosis and efferocytosis, independently of cyclooxygenase inhibition. In conclusion, combining repositioning with advances in G-protein coupled receptor biology (allosterism) may lead to potential new therapeutics. In addition, MC PAMs emerged as a viable approach to the development of innovative therapeutics for joint diseases.
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http://dx.doi.org/10.1007/s00018-016-2419-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346439PMC
April 2017

An orally administered butyrate-releasing derivative reduces neutrophil recruitment and inflammation in dextran sulphate sodium-induced murine colitis.

Br J Pharmacol 2017 06 3;174(11):1484-1496. Epub 2016 Nov 3.

Department of Pharmacy, University of Naples Federico II, Naples, Italy.

Background And Purpose: Butyrate has shown benefits in inflammatory bowel diseases. However, it is not often administered orally because of its rancid smell and unpleasant taste. The efficacy of a more palatable butyrate-releasing derivative, N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), was evaluated in a mouse model of colitis induced by dextran sodium sulphate (DSS).

Experimental Approach: Male 10 week-old BALB/c mice received DSS (2.5%) in drinking water (for 5 days) followed by DSS-free water for 7 days (DSS group). Oral FBA administration (42.5 mg·kg ) was started 7 days before DSS as preventive (P-FBA), or 2 days after DSS as therapeutic (T-FBA); both treatments lasted 19 days. One DSS-untreated group received only tap water (CON).

Key Results: FBA treatments reduced colitis symptoms and colon damage. P-FBA and T-FBA significantly decreased polymorphonuclear cell infiltration score compared with the DSS group. FBA reversed the imbalance between pro- and anti-inflammatory cytokines (reducing inducible NOS protein expression, CCL2 and IL-6 transcripts in colon and increasing TGFβ and IL-10). Morever, P-FBA and T-FBA limited neutrophil recruitment (by expression and localization of the neutrophil granule protease Ly-6G), restored deficiency of the butyrate transporter and improved intestinal epithelial integrity, preventing tight-junction impairment (zonulin-1 and occludin). FBA, similar to its parental compound sodium butyrate, inhibited histone deacetylase-9 and restored H3 histone acetylation, exerting an anti-inflammatory effect through NF-κB inhibition and the up-regulation of PPARγ.

Conclusions And Implications: FBA reduces inflammatory intestinal damage in mice indicating its potential as a postbiotic derivative without the problems associated with the oral administration of sodium butyrate.

Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
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http://dx.doi.org/10.1111/bph.13637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429328PMC
June 2017

Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection.

FASEB J 2016 12 17;30(12):4033-4041. Epub 2016 Aug 17.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.

Alveolar bone loss is a result of an aggressive form of periodontal disease (PD) associated with Aggregatibacter actinomycetemcomitans (Aa) infection. PD is often observed with other systemic inflammatory conditions, including arthritis. Melanocortin peptides activate specific receptors to exert antiarthritic properties, avoiding excessing inflammation and modulating macrophage function. Recent work has indicated that melanocortin can control osteoclast development and function, but whether such protection takes place in infection-induced alveolar bone loss has not been investigated. The purpose of this study was to evaluate the role of melanocortin in Aa-induced PD. Mice were orally infected with Aa and treated with the melanocortin analog DTrp-γMSH or vehicle daily for 30 d. Then, periodontal tissue was collected and analyzed. Aa-infected mice treated with DTrp-γMSH presented decreased alveolar bone loss and a lower degree of neutrophil infiltration in the periodontium than vehicle-treated animals; these actions were associated with reduced periodontal levels of TNF-α, IFN-γ, and IL-17A. In vitro experiments with cells differentiated into osteoclasts showed that osteoclast formation and resorptive activity were attenuated after treatment with DTrp-γMSH. Thus, melanocortin agonism could represent an innovative way to tame overexuberant inflammation and, at the same time, preserve bone physiology, as seen after Aa infection.-Madeira, M. F. M., Queiroz-Junior, C. M., Montero-Melendez, T., Werneck, S. M. C., Corrêa, J. D., Soriani, F. M., Garlet, G. P., Souza, D. G., Teixeira, M. M., Silva, T. A., Perretti, M. Melanocortin agonism as a viable strategy to control alveolar bone loss induced by oral infection.
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http://dx.doi.org/10.1096/fj.201600790RDOI Listing
December 2016

Resolution Pharmacology: Opportunities for Therapeutic Innovation in Inflammation.

Trends Pharmacol Sci 2015 Nov 2;36(11):737-755. Epub 2015 Nov 2.

William Harvey Research Institute, Queen Mary University of London, London, UK.

Current medicines for the clinical management of inflammatory diseases act by inhibiting specific enzymes or antagonising specific receptors or blocking their ligands. In the past decade, a new paradigm in our understanding of the inflammatory process has emerged with the appreciation of genetic, molecular, and cellular mechanisms that are engaged to actively resolve inflammation. The 'resolution of acute inflammation' is enabled by counter-regulatory checkpoints to terminate the inflammatory reaction, promoting healing and repair. It may be possible to harness this knowledge for innovative approaches to the treatment of inflammatory pathologies. Here we discuss current translational attempts to develop agonists at proresolving targets as a strategy to rectify chronic inflammatory status. We reason this new approach will lead to the identification of better drugs that will establish a new branch of pharmacology, 'resolution pharmacology'.
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http://dx.doi.org/10.1016/j.tips.2015.07.007DOI Listing
November 2015

Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions.

PLoS Biol 2015 Jul 16;13(7):e1002202. Epub 2015 Jul 16.

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom.

Lactate has long been considered a "waste" by-product of cell metabolism, and it accumulates at sites of inflammation. Recent findings have identified lactate as an active metabolite in cell signalling, although its effects on immune cells during inflammation are largely unexplored. Here we ask whether lactate is responsible for T cells remaining entrapped in inflammatory sites, where they perpetuate the chronic inflammatory process. We show that lactate accumulates in the synovia of rheumatoid arthritis patients. Extracellular sodium lactate and lactic acid inhibit the motility of CD4+ and CD8+ T cells, respectively. This selective control of T cell motility is mediated via subtype-specific transporters (Slc5a12 and Slc16a1) that we find selectively expressed by CD4+ and CD8+ subsets, respectively. We further show both in vitro and in vivo that the sodium lactate-mediated inhibition of CD4+ T cell motility is due to an interference with glycolysis activated upon engagement of the chemokine receptor CXCR3 with the chemokine CXCL10. In contrast, we find the lactic acid effect on CD8+ T cell motility to be independent of glycolysis control. In CD4+ T helper cells, sodium lactate also induces a switch towards the Th17 subset that produces large amounts of the proinflammatory cytokine IL-17, whereas in CD8+ T cells, lactic acid causes the loss of their cytolytic function. We further show that the expression of lactate transporters correlates with the clinical T cell score in the synovia of rheumatoid arthritis patients. Finally, pharmacological or antibody-mediated blockade of subtype-specific lactate transporters on T cells results in their release from the inflammatory site in an in vivo model of peritonitis. By establishing a novel role of lactate in control of proinflammatory T cell motility and effector functions, our findings provide a potential molecular mechanism for T cell entrapment and functional changes in inflammatory sites that drive chronic inflammation and offer targeted therapeutic interventions for the treatment of chronic inflammatory disorders.
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http://dx.doi.org/10.1371/journal.pbio.1002202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504715PMC
July 2015

ACTH: The forgotten therapy.

Semin Immunol 2015 May 26;27(3):216-26. Epub 2015 Feb 26.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, United Kingdom. Electronic address:

Although anti-inflammatory drugs are among the most common class of marketed drugs, chronic inflammatory conditions such as rheumatoid arthritis, multiple sclerosis or inflammatory bowel disease still represent unmet needs. New first-in-class drugs might be discovered in the future but the repurpose and further development of old drugs also offers promise for these conditions. This is the case of the melanocortin adrenocorticotropin hormone, ACTH, used in patients since 1952 but regarded as the last therapeutic option when other medications, such as glucocorticoids, cannot be used. Better understanding on its physiological and pharmacological mechanisms of actions and new insights on melanocortin receptors biology have revived the interest on rescuing this old and effective drug. ACTH does not only induce cortisol production, as previously assumed, but it also exerts anti-inflammatory actions by targeting melanocortin receptors present on immune cells. The endogenous agonists for these receptors (ACTH, α-, β-, and γ-melanocyte stimulating hormones), are also produced locally by immune cells, indicating the existence of an endogenous anti-inflammatory tissue-protective circuit involving the melanocortin system. These findings suggested that new ACTH-like melanocortin drugs devoid of steroidogenic actions, and hence side effects, could be developed. This review summarizes the actions of ACTH and melanocortin drugs, their role as endogenous pro-resolving mediators, their current clinical use and provides an overview on how recent advances on GPCR functioning may lead to a novel class of drugs.
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http://dx.doi.org/10.1016/j.smim.2015.02.003DOI Listing
May 2015

Biased agonism as a novel strategy to harness the proresolving properties of melanocortin receptors without eliciting melanogenic effects.

J Immunol 2015 Apr 27;194(7):3381-8. Epub 2015 Feb 27.

William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom; and

There is a need for novel approaches to control pathologies with overexuberant inflammatory reactions. Targeting melanocortin (MC) receptors represents a promising therapy for obesity and chronic inflammation, but lack of selectivity and safety concerns limit development. A new way to increase selectivity of biological effects entails the identification of biased agonists. In this study, we characterize the small molecule AP1189 as a biased agonist at receptors MC1 and MC3. Although not provoking canonical cAMP generation, AP1189 addition to MC1 or MC3, but not empty vector, transfected HEK293 cells caused ERK1/2 phosphorylation, a signaling responsible for the proefferocytic effect evoked in mouse primary macrophages. Added to macrophage cultures, AP1189 reduced cytokine release, an effect reliant on both MC1 and MC3 as evident from the use of Mc1r(-/-) and Mc3r(-/-) macrophages. No melanogenesis was induced by AP1189 in B16-F10 melanocytes. In vivo, oral AP1189 elicited anti-inflammatory actions in peritonitis and, upon administration at the peak of inflammation, accelerated the resolution phase by ∼3-fold. Finally, given the clinical efficacy of adrenocorticotropin in joint diseases, AP1189 was tested in experimental inflammatory arthritis, where this biased agonist afforded significant reduction of macroscopic and histological parameters of joint disruption. These proof-of-concept analyses with AP1189, an active oral anti-inflammatory and resolution-promoting compound, indicate that biased agonism at MC receptors is an innovative, viable approach to yield novel anti-inflammatory molecules endowed with a more favorable safety profile.
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http://dx.doi.org/10.4049/jimmunol.1402645DOI Listing
April 2015

Association between periodontal disease and inflammatory arthritis reveals modulatory functions by melanocortin receptor type 3.

Am J Pathol 2014 Aug 27;184(8):2333-41. Epub 2014 Jun 27.

The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. Electronic address:

Because there is clinical evidence for an association between periodontal disease and rheumatoid arthritis, it is important to develop suitable experimental models to explore pathogenic mechanisms and therapeutic opportunities. The K/BxN serum model of inflammatory arthritis was applied using distinct protocols, and modulation of joint disruption afforded by dexamethasone and calcitonin was established in comparison to the melanocortin (MC) receptor agonist DTrp(8)-γ-melanocyte stimulating hormone (MSH; DTrp). Wild-type and MC receptor type 3 (MC3)-null mice of different ages were also used. There was significant association between severity of joint disease, induced with distinct protocols and volumes of the arthritogenic K/BxN serum, and periodontal bone damage. Therapeutic treatment with 10 μg dexamethasone, 30 ng elcatonin, and 20 μg DTrp per mouse revealed unique and distinctive pharmacological properties, with only DTrp protecting both joint and periodontal tissue. Further analyses in nonarthritic animals revealed higher susceptibility to periodontal bone loss in Mc3r(-/-) compared with wild-type mice, with significant exacerbation at 14 weeks of age. These data reveal novel protective properties of endogenous MC3 on periodontal status in health and disease and indicate that MC3 activation could lead to the development of a new genus of anti-arthritic bone-sparing therapeutics.
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http://dx.doi.org/10.1016/j.ajpath.2014.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116693PMC
August 2014

Gapdh gene expression is modulated by inflammatory arthritis and is not suitable for qPCR normalization.

Inflammation 2014 Aug;37(4):1059-69

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK,

Gene expression studies are fundamental for the understanding of complex diseases, providing new insights into the pathogenic process and new tools for diagnostic and patient stratification. Gene profiling studies by real-time PCR require the use of reference genes for normalization and an appropriate validation is essential for accurate results. We performed a comprehensive assessment of six common housekeeping genes in the K/BxN serum-induced arthritis model in mice. Classical statistics and NormFinder analyses pointed out Gapdh as the less stable and therefore unsuitable as a reference control. Gapdh was considerably down-regulated in arthritic joints and therefore produced an overestimation of transcriptional changes. Hptr, B2m, and Rpl13a showed the most constant expression. Collectively our data advise against the use of Gapdh in gene expression studies in the acute phase of the K/BxN model and adds a cautionary note on the need to validate the reference genes for reliable, comparable, and reproducible results.
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http://dx.doi.org/10.1007/s10753-014-9829-xDOI Listing
August 2014

Microparticle alpha-2-macroglobulin enhances pro-resolving responses and promotes survival in sepsis.

EMBO Mol Med 2014 01 15;6(1):27-42. Epub 2013 Dec 15.

Centre for Biochemical Pharmacology The William Harvey Research Institute, Barts and The London School of Medicine Queen Mary University of London, London, UK.

Incorporation of locally produced signaling molecules into cell-derived vesicles may serve as an endogenous mediator delivery system. We recently reported that levels alpha-2-macroglobulin (A2MG)-containing microparticles are elevated in plasma from patients with sepsis. Herein, we investigated the immunomodulatory actions of A2MG containing microparticles during sepsis. Administration of A2MG-enriched (A2MG-E)-microparticles to mice with microbial sepsis protected against hypothermia, reduced bacterial titers, elevated immunoresolvent lipid mediator levels in inflammatory exudates and reduced systemic inflammation. A2MG-E microparticles also enhanced survival in murine sepsis, an action lost in mice transfected with siRNA for LRP1, a putative A2MG receptor. In vitro, A2MG was functionally transferred onto endothelial cell plasma membranes from microparticles, augmenting neutrophil-endothelial adhesion. A2MG also modulated human leukocyte responses: enhanced bacterial phagocytosis, reactive oxygen species production, cathelicidin release, prevented endotoxin induced CXCR2 downregulation and preserved neutrophil chemotaxis in the presence of LPS. A significant association was also found between elevated plasma levels of A2MG-containing microparticles and survival in human sepsis patients. Taken together, these results identify A2MG enrichment in microparticles as an important host protective mechanism in sepsis.
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http://dx.doi.org/10.1002/emmm.201303503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936490PMC
January 2014

Connections in pharmacology: innovation serving translational medicine.

Drug Discov Today 2014 Jul 6;19(7):820-3. Epub 2013 Dec 6.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

There is a paucity of molecules that progress through the drug development pipeline, making the drug discovery process expensive and frustrating. Innovative approaches to drug development are therefore required to maximise opportunities. Strategies such as the Connectivity Map (CMap), which compares >7000 gene expression signatures generated from more than 1000 drugs, can produce associations between currently unrelated therapeutics, unveiling new mechanisms of action and favouring drug repositioning. Here, we discuss these opportunities that could aid the drug development process and propose rigorous publication of 'omics data with open access and data sharing. We, pharmacologists of the third millennium, must aim towards maximising knowledge in an unbiased and cost-effective manner, to deliver new drugs for the global benefit of patients.
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http://dx.doi.org/10.1016/j.drudis.2013.11.022DOI Listing
July 2014

Identification of novel predictor classifiers for inflammatory bowel disease by gene expression profiling.

PLoS One 2013 14;8(10):e76235. Epub 2013 Oct 14.

The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.

Background: Improvement of patient quality of life is the ultimate goal of biomedical research, particularly when dealing with complex, chronic and debilitating conditions such as inflammatory bowel disease (IBD). This is largely dependent on receiving an accurate and rapid diagnose, an effective treatment and in the prediction and prevention of side effects and complications. The low sensitivity and specificity of current markers burden their general use in the clinical practice. New biomarkers with accurate predictive ability are needed to achieve a personalized approach that take the inter-individual differences into consideration.

Methods: We performed a high throughput approach using microarray gene expression profiling of colon pinch biopsies from IBD patients to identify predictive transcriptional signatures associated with intestinal inflammation, differential diagnosis (Crohn's disease or ulcerative colitis), response to glucocorticoids (resistance and dependence) or prognosis (need for surgery). Class prediction was performed with self-validating Prophet software package.

Results: Transcriptional profiling divided patients in two subgroups that associated with degree of inflammation. Class predictors were identified with predictive accuracy ranging from 67 to 100%. The expression accuracy was confirmed by real time-PCR quantification. Functional analysis of the predictor genes showed that they play a role in immune responses to bacteria (PTN, OLFM4 and LILRA2), autophagy and endocytocis processes (ATG16L1, DNAJC6, VPS26B, RABGEF1, ITSN1 and TMEM127) and glucocorticoid receptor degradation (STS and MMD2).

Conclusions: We conclude that using analytical algorithms for class prediction discovery can be useful to uncover gene expression profiles and identify classifier genes with potential stratification utility of IBD patients, a major step towards personalized therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076235PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796518PMC
June 2014

Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses.

Proc Natl Acad Sci U S A 2013 Nov 9;110(45):18232-7. Epub 2013 Oct 9.

William Harvey Research Institute, Barts and The London School of Medicine, London EC1M 6BQ, United Kingdom.

Formyl-peptide receptor type 2 (FPR2), also called ALX (the lipoxin A4 receptor), conveys the proresolving properties of lipoxin A4 and annexin A1 (AnxA1) and the proinflammatory signals elicited by serum amyloid protein A and cathelicidins, among others. We tested here the hypothesis that ALX might exist as homo- or heterodimer with FPR1 or FPR3 (the two other family members) and operate in a ligand-biased fashion. Coimmunoprecipitation and bioluminescence resonance energy transfer assays with transfected HEK293 cells revealed constitutive dimerization of the receptors; significantly, AnxA1, but not serum amyloid protein A, could activate ALX homodimers. A p38/MAPK-activated protein kinase/heat shock protein 27 signaling signature was unveiled after AnxA1 application, leading to generation of IL-10, as measured in vitro (in primary monocytes) and in vivo (after i.p. injection in the mouse). The latter response was absent in mice lacking the ALX ortholog. Using a similar approach, ALX/FPR1 heterodimerization evoked using the panagonist peptide Ac2-26, identified a JNK-mediated proapoptotic path that was confirmed in primary neutrophils. These findings provide a molecular mechanism that accounts for the dual nature of ALX and indicate that agonist binding and dimerization state contribute to the conformational landscape of FPRs.
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http://dx.doi.org/10.1073/pnas.1308253110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831442PMC
November 2013

Curbing Inflammation through Endogenous Pathways: Focus on Melanocortin Peptides.

Int J Inflam 2013 7;2013:985815. Epub 2013 May 7.

William Harvey Research Institute, Barts and The London School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.

The resolution of inflammation is now known to be an active process, armed with a multitude of mediators both lipid and protein in nature. Melanocortins are peptides endowed with considerable promise with their proresolution and anti-inflammatory effects in preclinical models of inflammatory disease, with tissue protective effects. These peptides and their targets are appealing because they can be seen as a natural way of inducing these effects as they harness endogenous pathways of control. Whereas most of the information generated about these mediators derives from several acute models of inflammation (such as zymosan induced peritonitis), there is some indication that these mediators may inhibit chronic inflammation by modulating cytokines, chemokines, and leukocyte apoptosis. In addition, proresolving mediators and their mimics have often been tested alongside therapeutic protocols, hence have been tested in settings more relevant to real life clinical scenarios. We provide here an overview on some of these mediators with a focus on melanocortin peptides and receptors, proposing that they may unveil new opportunities for innovative treatments of inflammatory arthritis.
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http://dx.doi.org/10.1155/2013/985815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664505PMC
June 2013

Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties.

Mol Cell Proteomics 2013 Aug 8;12(8):2205-19. Epub 2013 May 8.

The William Harvey Research Institute, Barts and The London School of Medical, Charterhouse Square, London EC1M 6BQ, United Kingdom.

Altered plasma neutrophil microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Herein, we investigate the proteome of neutrophil microparticles in order to shed light on their biological actions. Stimulation of human neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >400 distinct proteins with only 223 being shared by the two subsets. For instance, postadherent microparticles were enriched in alpha-2 macroglobulin and ceruloplasmin, whereas microparticles produced by neutrophils in suspension were abundant in heat shock 70 kDa protein 1. Annexin A1 and lactotransferrin were expressed in both microparticle subsets. We next determined relative abundance of these proteins in three types of human microparticle samples: healthy volunteer plasma, plasma of septic patients and skin blister exudates finding that these proteins were differentially expressed on neutrophil microparticles from these samples reflecting in part the expression profiles we found in vitro. Functional assessment of the neutrophil microparticles subsets demonstrated that in response to direct stimulation neutrophil microparticles produced reactive oxygen species and leukotriene B4 as well as locomoted toward a chemotactic gradient. Finally, we investigated the actions of the two neutrophil microparticles subsets described herein on target cell responses. Microarray analysis with human primary endothelial cells incubated with either microparticle subset revealed a discrete modulation of endothelial cell gene expression profile. These findings demonstrate that neutrophil microparticles are heterogenous and can deliver packaged information propagating the activation status of the parent cell, potentially exerting novel and fundamental roles both under homeostatic and disease conditions.
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http://dx.doi.org/10.1074/mcp.M113.028589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734580PMC
August 2013

Adipose tissue-specific modulation of galectin expression in lean and obese mice: evidence for regulatory function.

Obesity (Silver Spring) 2013 Feb;21(2):310-9

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois, USA.

Objective: Galectins (Gal) exert many activities, including regulation of inflammation and adipogenesis. We evaluated modulation of Gal-1, -3, -9 and -12 in visceral (VAT) and subcutaneous (SAT) adipose tissue in mice.

Design And Methods: We used two mouse models of obesity, high-fat diet induced obesity (DIO) and ob/ob mice. We also evaluated the response of Gal-1 KO mice to DIO.

Results: Both age and diet modulated expression of galectins, with DIO mice having higher serum Gal-1 and Gal-3 versus lean mice after 13-17 weeks of high-fat diet. In DIO mice there was a progressive increase in expression of Gal-1 and Gal-9 in SAT, whereas Gal-3 increased in both VAT and SAT. Expression of Gal-12 declined over time in VAT of DIO mice, similar to adiponectin. Obesity lead to increased production of Gal-1 in adipocytes, whereas the increased Gal-3 and Gal-9 of obesity mostly derived from the stromovascular fraction. Expression of Gal-12 was restricted to adipocytes. There was increased production of Gal-3 and Gal-9, but not Gal-1, in CD11c(-) and CD11c(+) macrophages from VAT of DIO versus lean mice. Expression of Gal-1, -3 and -12 in VAT and SAT of ob/ob mice followed a trend comparable to DIO mice. Rosiglitazone reduced serum Gal-1, but not Gal-3 and modulated expression of Gal-3 in VAT and Gal-9 and Gal-12 in SAT of DIO mice. High-fat feeding lead to increased adiposity in Gal-1 KO versus WT mice, with loss of correlation between leptin and adiposity and no alterations in glucose and insulin levels.

Conclusions: Obesity leads to differential modulation of Gal-1, 3, 9 and 12 in VAT and SAT, with Gal-1 acting as a modulator of adiposity.
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http://dx.doi.org/10.1002/oby.20016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610793PMC
February 2013

The calcitonin and glucocorticoids combination: mechanistic insights into their class-effect synergy in experimental arthritis.

PLoS One 2013 5;8(2):e54299. Epub 2013 Feb 5.

The William Harvey Research Institute, Barts and The London School of Medicine, London, United Kingdom.

Introduction: Previous work reported the anti-arthritic synergy afforded by combining calcitonin (CT) and glucocorticoids (GC). Here we focus on the pairing of elcatonin (eCT) and dexamethasone (Dex), querying whether: i) this was a class-effect action; ii) mechanistic insights could be unveiled; iii) the synergy affected canonical GC adverse effects.

Methods: Using the rat collagen-induced arthritis model, different combinations of eCT and Dex, were administered from disease onset to peak (day 11 to 18). Macroscopic disease score was monitored throughout, with biochemical and histological analyses conducted on plasma and tissues at day 18. The effect on acute hyperglycaemia and liver enzyme message were also assessed.

Results: Whilst eCT alone was inactive, it synergised at 1 µg/kg with low doses of Dex (7.5 or 15 µg/kg) to yield an anti-arthritic efficacy equivalent to a 4- to 7-fold higher Dex dose. Mechanistically, the anti-arthritic synergy corresponded to a marked attenuation in RA-relevant analytes. CXCL5 expression, in both plasma and joint, was markedly inhibited by the co-therapy. Finally, co-administration of eCT did not exacerbate metrics of GC adverse effects, and rescued some of them.

Conclusions: We present evidence of a class-effect action for the anti-arthritic synergy of CT/GC combination, underpinned by the powerful inhibition of joint destruction markers. Furthermore, we identify CXCL5 as a marker for the combination therapy with potential diagnostic and prognostic utility. Substantial GC dose reduction, together with the absence of exacerbated adverse effects, indicated a significant clinical potential for this co-therapy in RA and beyond.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054299PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564948PMC
August 2013

The antioxidant effect of β-caryophyllene protects rat liver from carbon tetrachloride-induced fibrosis by inhibiting hepatic stellate cell activation.

Br J Nutr 2013 Feb 1;109(3):394-401. Epub 2012 May 1.

Instituto de Nutrición y Tecnología de los Alimentos, Centro de Investigación Biomédica, Armilla, Spain.

Plant-based whole foods provide thousands of bioactive metabolites to the human diet that reduce the risk of developing chronic diseases. β-Caryophyllene (CAR) is a common constituent of the essential oil of numerous plants, vegetables, fruits and medicinal herbs, and has been used as a flavouring agent since the 1930 s. Here, we report the antioxidant activity of CAR, its protective effect on liver fibrosis and its inhibitory capacity on hepatic stellate cell (HSC) activation. CAR was tested for the inhibition of lipid peroxidation and as a free radical scavenger. CAR had higher inhibitory capacity on lipid peroxidation than probucol, α-humulene and α-tocopherol. Also, CAR showed high scavenging activities against hydroxyl radical and superoxide anion. The activity of 5-lipoxygenase, an enzyme that actively participates in fibrogenesis, was significantly inhibited by CAR. Carbon tetrachloride-treated rats received CAR at 2, 20 and 200 mg/kg. CAR significantly improved liver structure, and reduced fibrosis and the expression of Col1a1, Tgfb1 and Timp1 genes. Oxidative stress was used to establish a model of HSC activation with overproduction of extracellular matrix proteins. CAR (1 and 10 μm) increased cell viability and significantly reduced the expression of fibrotic marker genes. CAR, a sesquiterpene present in numerous plants and foods, is as a natural antioxidant that reduces carbon tetrachloride-mediated liver fibrosis and inhibits hepatic cell activation.
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http://dx.doi.org/10.1017/S0007114512001298DOI Listing
February 2013

Annexin A1 N-terminal derived Peptide ac2-26 exerts chemokinetic effects on human neutrophils.

Front Pharmacol 2012 28;3:28. Epub 2012 Feb 28.

William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London London, UK.

It is postulated that peptides derived from the N-terminal region of Annexin A1, a glucocorticoid-regulated 37-kDa protein, could act as biomimetics of the parent protein. However, recent evidence, amongst which the ability to interact with distinct receptors other then that described for Annexin A1, suggest that these peptides might fulfill other functions at variance to those reported for the parent protein. Here we tested the ability of peptide Ac2-26 to induce chemotaxis of human neutrophils, showing that this peptide can elicit responses comparable to those produced by the canonical activator formyl-Met-Leu-Phe (or FMLP). However, whilst disruption of the chemical gradient abolished the FMLP response, addition of peptide Ac2-26 in the top well of the chemotaxis chamber did not affect (10 μM) or augmented (at 30 μM) the neutrophil locomotion to the bottom well, as elicited by 10 μM peptide Ac2-26. Intriguingly, the sole addition of peptide Ac2-26 in the top wells produced a marked migration of neutrophils. A similar behavior was observed when human primary monocytes were used. Thus, peptide Ac2-26 is a genuine chemokinetic agent toward human blood leukocytes. Neutralization strategies indicated that engagement of either the GPCR termed FPR1 or its cognate receptor FPR2/ALX was sufficient to sustain peptide Ac2-26 induced neutrophil migration. Similarly, application of pharmacological inhibitors showed that cell locomotion to peptide Ac2-26 was mediated primarily by the ERK, but not the JNK and p38 pathways. In conclusion, we report here novel in vitro properties for peptide Ac2-26, promoting neutrophil and monocyte chemokinesis; a process that may contribute to accelerate the resolution phase of inflammation. We postulate that the generation of Annexin A1 N-terminal peptides at the site of inflammation may expedite the egress of migrated leukocytes thus promoting the return to homeostasis.
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http://dx.doi.org/10.3389/fphar.2012.00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288723PMC
October 2012

Molecular engineering of short half-life small peptides (VIP, αMSH and γ₃MSH) fused to latency-associated peptide results in improved anti-inflammatory therapeutics.

Ann Rheum Dis 2012 Jan 13;71(1):143-9. Epub 2011 Oct 13.

Bone and Joint Research Unit, William Harvey Research Institute, London, UK.

Objective: To facilitate the targeting to inflammation sites of small anti-inflammatory peptides, with short half-lives, by fusion with the latency-associated peptide (LAP) of transforming growth factor β1 through a cleavable matrix metalloproteinase (MMP) linker. This design improves efficacy, overcoming the limitations to their clinical use.

Methods: We generated latent forms of vasoactive intestinal peptide (VIP), α-melanocyte-stimulating hormone (MSH) and γ(3)MSH by fusion to LAP through an MMP cleavage site using recombinant DNA technology. The biological activities of these latent therapeutics were studied in vivo using monosodium urate (MSU)-induced peritonitis and collagen-induced arthritis (CIA) models. We assessed gene therapy and purified protein therapy.

Results: The recruitment of the polymorphonuclear cells induced by MSU injection into mouse peritoneal cavity was reduced by 35% with γ(3)MSH (1 nmol), whereas administration of a much lower dose of purified latent LAP-MMP-γ(3)MSH (0.03 nmol) attenuated leucocyte influx by 50%. Intramuscular gene delivery of plasmids coding LAP-MMP-VIP and LAP-MMP-αMSH at disease onset reduced the development of CIA compared with LAP-MMP, which does not contain any therapeutic moiety. Histological analysis confirmed a significantly lower degree of inflammation, bone and cartilage erosion in groups treated with LAP-MMP-VIP or LAP-MMP-αMSH. Antibody titres to collagen type II and inflammatory cytokine production were also reduced in these two groups.

Conclusion: Incorporation of small anti-inflammatory peptides within the LAP shell and delivered as recombinant protein or through gene therapy can control inflammatory and arthritic disease. This platform delivery can be developed to control human arthritides and other autoimmune diseases.
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http://dx.doi.org/10.1136/annrheumdis-2011-200100DOI Listing
January 2012

The melanocortin agonist AP214 exerts anti-inflammatory and proresolving properties.

Am J Pathol 2011 Jul 10;179(1):259-69. Epub 2011 May 10.

The William Harvey Research Institute, Barts, and The London School of Medicine, Queen Mary University of London, London, United Kingdom.

Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 μg/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC(1), mutant mice but lost in MC(3) null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1β, tumor necrosis factor-α, and IL-6, respectively. Inhibition of IL-1β release was retained in MC(1) mutant cells but was lost in MC(3) null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC(3) null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo. Finally, in a model of inflammatory arthritis, AP214 evoked significant reductions in the clinical score. These results indicate that AP214 elicits anti-inflammatory responses, with a preferential effect on IL-1β release. Furthermore, we describe for the first time a positive modulation of an MC agonist on the process of efferocytosis. In all cases, endogenous MC(3) is the receptor that mediates these novel properties of AP214. These findings might clarify the tissue-protective properties of AP214 in clinical settings and may open further development for novel MC agonists.
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http://dx.doi.org/10.1016/j.ajpath.2011.03.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123798PMC
July 2011

Role of melanocortin receptors in the regulation of gouty inflammation.

Curr Rheumatol Rep 2011 Apr;13(2):138-45

William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.

Gouty arthritis is a form of acute joint inflammation provoked by joint deposition of urate crystals. Although this acute pathology resolves after a few days, the marked degree of inflammation in the joint and--possibly more important to the patient--the excruciating pain it causes require proper therapeutic management. Often deemed a "poor sibling" of chronic joint pathologies such as rheumatoid arthritis and psoriatic arthritis, the increasing incidence of gout makes it a more palatable disease for novel drug discovery programs. This fact, associated with novel insights into the molecular mechanisms activated by the urate crystal deposition, is at the basis of new therapeutics under clinical development for gout, a valid example being the effective targeting of the proinflammatory cytokine interleukin-1. Here we briefly review the current status of antigout drug development and propose another target; our focus is on melanocortin receptor agonists as novel therapeutics for gout and inflammatory arthritides, a prototype of which, the adrenocorticotropic hormone, is already used in clinical settings.
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http://dx.doi.org/10.1007/s11926-011-0163-0DOI Listing
April 2011

Melanocortin control of cell trafficking in vascular inflammation.

Adv Exp Med Biol 2010 ;681:88-106

The William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ.

Over 20 years of research based upon application of experimental models of inflammation and tissue injury have revealed exquisite controlling functions for melanocortin hormones and, subsequently, their synthetic derivatives. More recent discoveries have shed light on the receptor targets responsible for these effects, leading to what could be the next step-change for this line of research, the development of novel therapeutics for the control of human inflammatory pathologies. Here we review some of this work with particular emphasis on more recent studies that have substantiated the activities of melanocortin peptides to reveal important regulatory functions for their receptors in vascular inflammation and disease models. Moreover, we summarise the drug discovery activities (for what is published knowledge) attempting to capitalise on this wealth of research on melanocortins, though we should not forget the successful employment of ACTH to treat human gouty arthritis. Altogether, this chapter would corroborate and flare the enthusiasm for this line of research, as we are confident that the right times might have arrived to develop novel anti-arthritic and tissue-protective compounds that will be acting by mimicking the way our endogenous melanocortins would act to exert their homeostatic and check-point functions.
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http://dx.doi.org/10.1007/978-1-4419-6354-3_7DOI Listing
September 2012

Melanocortin receptors as novel effectors of macrophage responses in inflammation.

Front Immunol 2011 13;2:41. Epub 2011 Sep 13.

William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London London, UK.

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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http://dx.doi.org/10.3389/fimmu.2011.00041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342072PMC
August 2012