Pathways to Melanoma Development: Lessons from the Mouse

Because of subtle differences between mouse and human skin, mice have traditionally not been an ideal model to study melanoma development. Understanding of the molecular mechanisms of melanoma predisposition, however, has been greatly improved by modeling various pathway defects in the mouse. This review analyzes the latest developments in mouse models of melanoma, and summarizes what these may indicate about the development of this neoplasm in humans. Mutations of genes involved in human melanoma have been recapitulated with some unexpected results, particularly with respect to the role of the two transcripts (Ink4a and Arf) encoded by the Cdkn2a locus. Both the Ink4a/pRb and Arf/p53 pathways are involved in melanoma development in mice, and possible mechanisms of cross-talk between the two pathways are discussed. We also know from mouse models that Ras/mitogen-activated protein kinase pathway activation is very important in melanoma development, either through direct activation of Ras (e.g., Hras G12V), or via activation of Ras-effector pathways by other oncogenes (e.g., Ret, Hgf/Sf). Ras can cooperate with the Arf/p53 pathway, and probably the Ink4a/Rb pathway, to induce melanoma. These three growth regulation pathways (Ink4a/pRb, Arf/p53, and Ras/mitogen-activated protein kinase) seem to represent three major axes of melanoma development in mice. Finally, we summarize experiments using genetically modified mice that have given indications of the intensity and timing of ultraviolet radiation exposure that may be most responsible for melanoma development.

Development of a novel titration and off-gas analysis (TOGA) sensor for study of biological processes in wastewater treatment systems

The development of the new TOGA (titration and off-gas analysis) sensor for the detailed study of biological processes in wastewater treatment systems is outlined. The main innovation of the sensor is the amalgamation of titrimetric and off-gas measurement techniques. The resulting measured signals are: hydrogen ion production rate (HPR), oxygen transfer rate (OTR), nitrogen transfer rate (NTR), and carbon dioxide transfer rate (CTR). While OTR and NTR are applicable to aerobic and anoxic conditions, respectively, HPR and CTR are useful signals under all of the conditions found in biological wastewater treatment systems, namely, aerobic, anoxic and anaerobic. The sensor is therefore a powerful tool for studying the key biological processes under all these conditions. A major benefit from the integration of the titrimetric and off-gas analysis methods is that the acid/base buffering systems, in particular the bicarbonate system, are properly accounted for. Experimental data resulting from the TOGA sensor in aerobic, anoxic, and anaerobic conditions demonstrates the strength of the new sensor. In the aerobic environment, carbon oxidation (using acetate as an example carbon source) and nitrification are studied. Both the carbon and ammonia removal rates measured by the sensor compare very well with those obtained from off-line chemical analysis. Further, the aerobic acetate removal process is examined at a fundamental level using the metabolic pathway and stoichiometry established in the literature, whereby the rate of formation of storage products is identified. Under anoxic conditions, the denitrification process is monitored and, again, the measured rate of nitrogen gas transfer (NTR) matches well with the removal of the oxidised nitrogen compounds (measured chemically). In the anaerobic environment, the enhanced biological phosphorus process was investigated. In this case, the measured sensor signals (HPR and CTR) resulting from acetate uptake were used to determine the ratio of the rates of carbon dioxide production by competing groups of microorganisms, which consequently is a measure of the activity of these organisms. The sensor involves the use of expensive equipment such as a mass spectrometer and requires special gases to operate, thus incurring significant capital and operational costs. This makes the sensor more an advanced laboratory tool than an on-line sensor. (C) 2003 Wiley Periodicals, Inc.

Waste recovery into activated carbon for water purification from heavy metals

Dissertação apresentada para obtenção do Grau de Doutor em Engenharia Química Pela Universidade Nova de Lisboa,Faculdade de Ciências e Tecn

Development of folate-targeted liposomes for rheumatoid arthritis therapy

Tese de Doutoramento em Biologia Molecular e Ambiental (área de especialização em Biologia Celular e Saúde).

The design and development of heat extraction technologies for the utilisation of compost thermal energy

A composting Heat Extraction Unit (HEU) was designed to utilise waste heat from decaying organic matter for a variety of heating application The aim was to construct an insulated small scale, sealed, organic matter filled container. In this vessel a process fluid within embedded pipes would absorb thermal energy from the hot compost and transport it to an external heat exchanger. Experiments were conducted on the constituent parts and the final design comprised of a 2046 litre container insulated with polyurethane foam and kingspan with two arrays of qualpex piping embedded in the compost to extract heat. The thermal energy was used in horticultural trials by heating polytunnels using a radiator system during a winter/spring period. The compost derived energy was compared with conventional and renewable energy in the form of an electric fan heater and solar panel. The compost derived energy was able to raise polytunnel temperatures to 2-3°C above the control, with the solar panel contributing no thermal energy during the winter trial and the electric heater the most efficient maintaining temperature at its preset temperature of 10°C. Plants that were cultivated as performance indicators showed no significant difference in growth rates between the heat sources. A follow on experiment conducted using special growing mats for distributing compost thermal energy directly under the plants (Radish, Cabbage, Spinach and Lettuce) displayed more successful growth patterns than those in the control. The compost HEU was also used for more traditional space heating and hot water heating applications. A test space was successfully heated over two trials with varying insulation levels. Maximum internal temperature increases of 7°C and 13°C were recorded for building U-values of 1.6 and 0.53 W/m2K respectively using the HEU. The HEU successfully heated a 60 litre hot water cylinder for 32 days with maximum water temperature increases of 36.5°C recorded. Total energy recovered from the 435 Kg of compost within the HEU during the polytunnel growth trial was 76 kWh which is 3 kWh/day for the 25 days when the HEU was activated. With a mean coefficient of performance level of 6.8 calculated for the HEU the technology is energy efficient. Therefore the compost HEU developed here could be a useful renewable energy technology particularly for small scale rural dwellers and growers with access to significant quantities of organic matter

Development of cell mediated immunity to flagellar antigens and acquired resistance to infection by Trypanosoma cruzi in mice

Modulation by BCG and/or cyclophosphamide of sensitization of mice with flagellar fraction (a tubulin-enriched fraction) prevented death of mice challenged with T. cruzi CL strain trypomastigotes recovered from Vero cells. A methodology was ceveloped to assay specific antigens and to determine optimal doses for sensitization and elicitation of DTH in mice. CL strain is predominantly myotropic strain which does not produce important parasitism of mononuclear phagocyte cells; these cells appear to control infection when activated in vivo. Maximum protection was seen in this study when BCG and cyclophosphamide were associated, but protection was observed also when cyclophosphamide, that prevents supressor T cells, was applied 2 days before flagellar fraction sensitization in normal mice. These experiments suggested that the macrophage may have an important role in the early phases of infection particularly when nonspecific stimulation is associated with specific sensitization. A correlation betwen delayed hypersensitivity to parasite antigens and protection was observed.

Role of intracellular signaling pathways activated in fibroblasts in response to lipoproteins

Summary The best described physiological function of low-density lipoproteins (LDL) is to transport cholesterol to target tissues. LDL deliver their cholesterol cargo to cells following their interaction with the LDL receptor. LDL, when their vascular concentrations increase, have also been implicated in pathologies such as atherosclerosis. Among the cell types that are found in blood vessels, endothelial and smooth muscle cells have dominated cellular research on atherosclerotic mechanisms and LDL activation of signaling pathways, while very little is known about adventitial fibroblast activation caused by elevated lipoprotein levels. Since fibroblasts participate in wound repair and since it has recently been recognized that fibroblasts may play pivotal roles in vascular remodeling and repair of injury, we assessed whether lipoproteins affect fibroblast function. We have found that LDL specifically mediate the activation of a class of mitogen-activated protein kinases (MAPKs): the p38 MAPKs. The activation of this pathway in turn modulates cell shape by promoting lamellipodia formation and extensive cell spreading. This is of particular interest because it provides a mechanism by which LDL can promote wound healing or vessel wall remodeling as observed during the development of atherosclerosis. In order to understand the molecular mechanisms by which LDL induce p38 activation we searched for the component in the LDL particle responsible for the induction of this pathway. We found that cholesterol is the major component of lipoprotein particles that mediates their ability to stimulate the p38 MAPK pathway. Furthermore, we investigated the cellular mechanisms underlying the ability of LDL to induce cell shape changes and whether this could participate in wound repair. Our recent data demonstrates that the capacity of LDL to induce fibroblast spreading relies on their ability to stimulate IL-8 secretion, which in turn leads to accelerated wound healing. LDL-induced IL-8 production and subsequent wound closure are impaired upon inhibition of the p38 MAPK pathway indicating that the LDL-induced spreading and accelerated wound sealing rely on the ability of LDL to stimulate IL-8 secretion in a p38 MAPK-dependent manner. Therefore, regulation of fibroblast shape and migration by lipoproteins may be relevant to atherosclerosis that is characterized by increased LDL-cholesterol levels, IL-8 production and extensive remodeling of the vessel wall. Résumé: La fonction physiologique des lipoprotéines à faible densité (LDL) la mieux décrite est celle du transport du cholestérol aux tissus cibles. Les LDL livrent leur cargaison de cholestérol aux cellules après leur interaction avec le récepteur au LDL. Une concentration vasculaire des LDL augmenté est également impliquée dans le développement de l'athérosclérose. Parmi les types de cellule présents dans les vaisseaux sanguins, les cellules endothéliales et les cellules du muscle lisse ont dominé la recherche cellulaire sur les mécanismes athérosclérotiques et sur l'activation par les LDL des voies de signalisation intracellulaire. A l'inverse peu de choses sont connues sur l'activation des fibroblastes de l'adventice par les lipoprotéines. Puisqu'il a été récemment reconnu que les fibroblastes peuvent jouer un rôle central dans la remodélisation vasculaire et la réparation tissulaire, nous avons étudié si les lipoprotéines affectent la fonction des fibroblastes. Nous avons constaté que les LDL activent spécifiquement une classe de protéines kinases: les p38 MAPK (mitogen-activated protein kinases). L'activation de cette voie module à son tour la forme de la cellule en favorisant la formation de lamellipodes et l'agrandissement des cellules. Cela a un intérêt particulier car il fournit un mécanisme par lequel les LDL peuvent promouvoir la cicatrisation ou la remodélisation des parois vasculaires comme observés lors du développement de l'athérosclérose. Pour comprendre les mécanismes moléculaires par lesquels les LDL provoquent l'activation des p38 MAPK, nous avons cherché à identifier les composants dans la particule de LDL responsables de l'induction de cette voie. Nous avons constaté que le cholestérol est l'élément principal des particules de lipoprotéine qui contrôle leur capacité à stimuler la voie des p38 MAPK. En outre, nous avons examiné les mécanismes cellulaires responsables de la capacité des LDL à induire des changements dans la forme des cellules. Nos données récentes démontrent que la capacité des LDL à induire l'agrandissement des cellules, ainsi que leur aptitude à favoriser la cicatrisation, reposant sur leur capacité à stimuler la sécrétiond'IL-8. La production d'IL-8 induite par les LDL est bloquée par l'inhibition de la voie p38 MAPK, ce qui indique que l'étalement des cellules induit par les LDL ainsi que l'accélération de la cicatrisation sont liés à la capacité des LDL à stimuler la sécrétion d'IL8 via l'activation des p38 MAPK. La régulation de la forme et de la migration des fibroblastes par les lipoprotéines peuvent donc participer au développement de l'athérosclérose qui est caractérisée par l'augmentation des niveaux de production de LDL-cholestérol et d'IL-8 ainsi que par une remodélisation augmentée de la paroi du vaisseau.

Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

Peroxisome proliferator-activated receptors beta/delta: emerging roles for a previously neglected third family member.

PURPOSE OF REVIEW: Peroxisome proliferator-activated receptors alpha, beta/delta and gamma are members of the nuclear receptor superfamily. They mediate the effects of fatty acids and their derivatives at the transcriptional level, and are considered to be lipid sensors that participate in the regulation of energy homeostasis. Compared with the alpha and gamma peroxisome proliferator-activated receptor isotypes, peroxisome proliferator-activated receptor beta functions have long remained an enigma. In this review, we focus on emerging knowledge about peroxisome proliferator-activated receptor beta activation and roles. RECENT FINDINGS: We review recent data that suggest key roles in basic cell functions, such as proliferation, differentiation and survival, and in embryonic development and lipid metabolism in peripheral tissues. SUMMARY: The newly unveiled roles of peroxisome proliferator-activated receptor beta in important basic cell functions certainly justify a further exploration of its potential as a therapeutic target in pathologies such as metabolic syndrome X or skin diseases.

Differential requirement for CD4 help in the development of an antigen-specific CD8+ T cell response depending on the route of immunization.

Previous studies in our laboratory have shown that DBA/2 mice injected i.p. with syngeneic P815 tumor cells transfected with the HLA-CW3 gene (P815-CW3) showed a dramatic expansion of activated CD8+CD62L- T cells expressing exclusively the Vbeta10 segment. We have used this model to study the regulatory mechanisms involved in the development of the CW3-specific CD8+ response, with respect to different routes of immunization. Whereas both intradermal (i.d.) and i.p. immunization of DBA/2 mice with P815-CW3 cells led to a strong expansion of CD8+CD62L-Vbeta10+ cells, only the i.d. route allowed this expansion after immunization with P815 cells transfected with a minigene coding for the antigenic epitope CW3 170-179 (P815 miniCW3). Furthermore, depletion of CD4+ T cells in vivo completely abolished the specific response of CD8+CD62L-Vbeta10+ cells and prevented the rejection of P815-CW3 tumor cells injected i.p., whereas it did not affect CD8S+CD62L-Vbeta10+ cell expansion after i.d. immunization with either P815-CW3 or P815 miniCW3. Finally, the CW3-specific CD8+ memory response was identical whether or not CD4+ T cells were depleted during the primary response. Collectively, these results suggest that the CD8+ T cell response to P815-CW3 tumor cells injected i.p. is strictly dependent upon recognition of a helper epitope by CD4+ T cells, whereas no such requirement is observed for i.d. injection.

Analysis of the regulation of Nodal function by SPC-mediated cleavage during early mammalian development

RÉSUMÉ Après implantation dans l'utérus, le foetus de mammifère est composé de trois populations différentes de cellules: l'epiblast, l'ectoderme extraembryonnaire et l'endoderme viscéral. Pendant la gastrulation, les cellules de l'epiblast donnent naissance aux trois lignées germinales: l'ectoderme, le mésoderme et l'endodermes. Les lignées germinales produisent par la suite les différents tissus et organes du corps embryonnaire et adulte. Les cellules de l'ectoderme extraembryonnaire donnent par la suite le composant foetal du placenta qui est essentiel à la survie de l'embryon dans l'utérus. L'épiblast et l'ectoderme extraembryonnaire sont entourés par l'endoderme viscéral et forment une structure connue sous le nom de bouton embryonnaire. L'endoderme viscéral joue un rôle important dans l'embryogenèse car il comporte une sous-population de cellules appelées l'endoderme viscéral antérieur dont les signaux influencent l'épiblast adjacent et déterminent le futur axe antéro-postérieur de l'embryon. La protéine de signalisation Nodal de la famille des TGFß est essentielle dans l'épiblast pour spécifier le mésendoderme, l'endoderme viscéral antérieur, ainsi que pour maintenir les cellules souche de l'ectoderme extraembryonnaire. Ainsi, dans les embryons mutants pour Nodal, aucun axe antéro-postérieur n'est établi, les lignées germinales ne sont pas spécifiés et le placenta ne se développe pas. Au niveau moléculaire, comme pour les protéines de la famille des TGFß, Nodal est initialement synthétisée sous forme de précurseur avant d'être clivée de façon endoproteolytique par des protéanes sécrétées, les proprotéines convertases du type subtilisin (SPC), qui suppriment la partie inhibitrice N-terminale du pro peptide. Dans ce contexte, le projet de ma thèse a été d'analyser l'influence des SPC sur la fonction de Nodal en employant une combinaison d'approches génétiques et biochimiques. Premièrement, nous avons constaté que le clivage du précurseur par les protéases active Nodal, mais en même temps augmente son turn-over et diminue la portée de son action. Deuxièmement, dans l'embryon, il apparaît que Nodal est activé par l'action combinée de Furin et de PACE4, deux protéases sécrétées qui sont spécifiquement exprimées dans les cellules de l'ectoderme extraembryonnaire, donc adjacentes au domaine d'expression de Nodal. De manière similaire aux mutants de Nodal, les embryons mutants pour les deux protéases ne forment pas d'endoderme viscéral antérieur et ne gastrulent pas. Cependant, certains gènes cible de Nodal restent exprimés, suggérant que toutes les activités de Nodal ne sont pas dépendent du clivage par les SPCs. En effet, la génération et l'analyse de mutants portant un allèle knock-in qui code pour une forme mutante de Nodal résistante aux SPC, ont montré que ces mutants ont les caractères phénotypique des mutants de Nodal seulement de façon partielle. La formation de mésoderme est partiellement induite, et de façon remarquable, la forme de Nodal résistante aux SPC est capable d'agir à une distance de sa source, maintenant l'expression de ses propres protéases et d'autres gènes essentiels pour la spécification de l'ectoderme extraembryonnaire. Ensemble, ces résultats prouvent que par leur action directe les protéases extraembryonnaire modulent la signalisation de Nodal pendant le développement mammifère précoce. SUMMARY : Early after implantation in the uterus, the mammalian conceptus is composed of three different cell populations: the epiblast, the extraembryonic ectoderm and the visceral endoderm. During gastrulation, epiblast cells give rise to the three embryonic germ layers: the ectoderm, the mesoderm and the endoderm. These germ layers then generate the different tissues and organs of the embryonic and adult bodies. In parallel, extraembryonic ectoderm cells give rise to the fetal component of the placenta, which is essential for the survival of the embryo in the uterus. Both the epiblast and extraembryonic ectoderm are surrounded by the visceral endoderm to form a structure known as the egg cylinder. The visceral endoderm plays an important role as it harbours a subpopulation of cells called the anterior visceral endoderm, from which signals influence the adjacent epiblast and determine the future antero-posterior embryonic axis. The TGFß-related signalling protein Nodal is required within the epiblast to specify the mesoderm, the endoderm,the anterior visceral endoderm and is also essential to maintain stem cells in the extraembryonic ectoderm. Thus, in Nodal null conceptuses, no antero-posterior axis is established, the germ layers are not specified and the placenta does not develop. At the molecular level, Nodal, like related proteins of the TGFß family, is initially synthesized as a precursor and undergoes endoproteolytic cleavage by secreted proteases of the subtilisin-like proprotein convertases (SPC) to remove an inhibitory N-terminal pro peptide. In the embryo, Nodal is activated by the combined action of Furin and PACE4, two secreted SPCs that are specifically expressed in cells of the extraembryonic ectoderm, thus adjacent to the Nodal expression domain. Similar to Nodal null .embryos, mutant embryos lacking both these proteases fail to specify the anterior visceral endoderm and to undergo gastrulation. However, these mutants still express a subset of Nodal target genes, suggesting that part of Nodal activity is independent on cleavage by SPCs. Indeed, by generating and analyzing mutants with a knock-in allele that encodes an SPC-resistant mutant form of Nodal, I could show that they retain a subset of Nodal activities. Mesoderm formation is partially induced, but most remarkably, SPC-resistant Nodal form is able to act at a distance from its source, maintaining the expression of its proteases and of other genes essential for maintenance of the extraembryonic ectoderm.

Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels.

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

Protease-activated receptors and inflammatory hyperalgesia

Recent advances in basic science pointed to a role for proteinases, through the activation of proteinase-activated receptors (PARs) in nociceptive mechanisms. Activation of PAR1, PAR2 and PAR4 either by proteinases or by selective agonists causes inflammation inducing most of the cardinal signs of inflammation: swelling, redness, and pain. Sub-inflammatory doses of PAR2 agonist still induced hyperalgesia and allodynia while PAR2 has been shown to be implicated in the generation of hyperalgesia in different inflammatory models. In contrast, sub-inflammatory doses of PAR1 increases nociceptive threshold, inhibiting inflammatory hyperalgesia, thereby acting as an analgesic agent. PARs are present and functional on sensory neurons, where they participate either directly or indirectly to the transmission and/or inhibition of nociceptive messages. Taken together, the results discussed in this review highlight proteinases as signaling molecules to sensory nerves. We need to consider proteinases and the receptors that are activated by proteinases as important potential targets for the development of analgesic drugs in the treatment of inflammatory pain.

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

The intestinal epithelium plays a crucial role in providing a barrier between the external environment and the internal milieu of the body. A compromised mucosal barrier is characteristic of mucosal inflammation and is a key determinant of the development of intestinal diseases such as Crohn's disease and ulcerative colitis. The intestinal epithelium is regularly exposed to serine proteinases and this exposure is enhanced in numerous disease states. Thus, it is important to understand how proteinase-activated receptors (PARs), which are activated by serine proteinases, can affect intestinal epithelial function. This review surveys the data which demonstrate the wide distribution of PARs, particularly PAR-1 and PAR-2, in the gastrointestinal tract and accessory organs, focusing on the epithelium and those cells which communicate with the epithelium to affect its function. PARs have a role in regulating secretion by epithelia of the salivary glands, stomach, pancreas and intestine. In addition, PARs located on subepithelial nerves, fibroblasts and mast cells have important implications for epithelial function. Recent data outline the importance of the cellular site of PAR expression, as PARs expressed on epithelia may have effects that are countered by PARs expressed on other cell types. Finally, PARs and their ability to promote epithelial cell proliferation are discussed in terms of colon cancer.

Peroxisome proliferator-activated receptor-beta as a target for wound healing drugs.

Healing of cutaneous wounds, which is crucial for survival after an injury, proceeds via a well-tuned pattern of events including inflammation, re-epithelialisation, and matrix and tissue remodelling. These events are regulated spatio-temporally by a variety of growth factors and cytokines. The inflammation that immediately follows injury increases the expression of peroxisome proliferator-activated receptor (PPAR)-beta in the wound edge keratinocytes and triggers the production of endogenous PPARbeta ligands that activate the newly produced receptor. This elevated PPARbeta activity results in increased resistance of the keratinocytes to the apoptotic signals released during wounding, allowing faster re-epithelialisation. The authors speculate that, in parallel, ligand activation of PPARbeta in infiltrated macrophages attenuates the inflammatory response, which also promotes repair. Thus, current understanding of the roles of PPARbeta in different cell types implicated in tissue repair has revealed an intriguing intercellular cross-talk that coordinates, spatially and temporally, inflammation, keratinocyte survival, proliferation and migration, which are all essential for efficient wound repair. These novel insights into the orchestrating roles of PPARbeta during wound healing may be helpful in the development of drugs for acute and chronic wound disorders.