Inflammation

Research Interests

The Inflammation Laboratory is located at the Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, 2780-156 Oeiras, Portugal. Inflammation is a beneficial host response to foreign challenge or tissue injury, leading to restoration of tissue structure and function. It is characterized by local and transient extravasation of soluble molecules and leukocytes from blood into non-lymphoid tissues. Inflammatory reactions are controlled via the coordinated expression of pro- and anti-inflammatory genes. Expression of pro-inflammatory genes promotes the "onset" of inflammatory reactions while expression of anti-inflammatory genes promotes their "resolution". Failure to express adequate levels of pro- or anti-inflammatory genes can lead to increased susceptibility to infectious diseases or to the development of “inflammatory diseases”, respectively. The research effort developed at the Inflammation laboratory is aimed at understanding the cellular and molecular mechanisms underlying the resolution of inflammatory reactions. Our body of work supports the notion that one of such mechanisms involves the expression of the stress responsive enzyme heme oxygenase-1 (HO-1). Under inflammatory conditions, HO-1 becomes the rate-limiting enzyme in the catabolism of heme, generating biliverdin, free Fe and the gas carbon monoxide (CO). All three end products contribute in a way or another to dampen inflammation.

The inflammation laboratory is seeking post doctoral fellows. If interested please send a letter of motivation, cv and two references to Miguel P. Soares at mpsoares@igc.gulbenkian.pt

Miguel Soares - CV

Group Members

Research Project

Molecular Mechanisms underlying the protective effect of HO-1 derived CO: Interaction with the NF-kappaB signal transduction pathway.

Activation of endothelial cells (EC), such as it occurs during microbial infection, is associated with the acquisition of a pro-inflammatory phenotype that assists the sequestration and activation of leukocytes into sites of infection. The pro-inflammatory phenotype of activated EC must be tightly controlled so that chronic inflammation does not develop. One of the mechanisms by which this occurs relies on the expression of "protective genes" that control not only the pro-inflammatory phenotype associated with EC activation but in addition protect EC from undergoing apoptosis. One of such genes is the stress responsive enzyme heme oxygenase-1 (HO-1). We have recently shown that HO-1 modulates the expression of the pro-inflammatory genes, E-selectin (CD62E) and vascular cell adhesion molecule-1 (VCAM-1/CD106). Regulation of the cellular pool of free iron, associated with the expression of HO-1 in EC, inhibits the activity of NF-kappaB, a transcription factor required for the expression of E-selectin and VCAM-1 in activated EC. The main focus of this project is to establish the mechanism via which modulation of free iron regulates NK-kappaB activation in EC.

Funding

European Community, 6th Framework - Grant LSH-2005-1.2.5-1
Application of post-genomics to xenotransplantation research
Coordinator: Emanuelle Cozzi
Institution: Azienda Ospedaliera di Padova.
Title: “Engineering of the porcine genome for xenotransplantation studies in primates: a step towards clinical application”, also known by the acronym of Xenome”. LINK

POCTI/BIA-BCM/56829/2004 - "Fundaçao para a Ciencia e Tecnologia"
Molecular Mechanisms Underlying the Protective Effect of Heme Oxygenase- 1: Interaction with the NF-kappaB Signal Transduction Pathway.

Collaborators

Department of Neurology and Neuroscience, Division of Neurobiology, Weill Medical College of Cornell University, New York, USA.
Josef Anrather LINK

Research Project

Molecular mechanisms underlying the anti-apoptotic effect of heme oxygense-1 (HO-1) and of its catalytic product carbon monoxide (CO).

The stress responsive gene heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. This effect probably accounts for the overall protective effect of HO-1, as EC apoptosis is a highly deleterious event. The anti-apoptotic effect of HO-1 is dependent on the generation of the gas carbon monoxide (CO), which occurs via the degradation of heme. CO protects EC from undergoing apoptosis via a mechanism that requires the activation of the p38 mitogen activated protein kinases (MAPK). The molecular mechanism(s) by which CO interact with this signaling transduction pathway and how this contributes to the anti-apoptotic effect of HO-1/CO remains to be established and is the focus of this project.

Collaborators

Harvard Medical School, Boston, USA.
Leo Otterbein LINK and Fritz H. Bach LINK

Imperial College London, Faculty of Medicine, School of Medicine, Endothelial cell cytoprotection group
Justin Masson, LINK

Research Project

Carbon monoxide suppresses the development of atherosclerotic lesions: Mechanism of action and possible therapeutic applications.

The hypothesis tested in this proposal is that inhaled CO can prevent the pathogenesis of atherosclerosis via a mechanism that involves the modulation of monocyte/macrophage activation as well as the inhibition of smooth muscle cell (SMC) proliferation. We have previously shown that inhaled CO prevents the development of intimal hyperplasia that originates from acute vascular injury, associated with organ transplantation and/or balloon injury. We have also shown that this effect is associated with the ability of CO to suppress the pro-inflammatory phenotype of monocyte/macrophage activation and to block SMC proliferation via a sequence of events that requires the activation of the p38 mitogen-activated protein kinases (MAPK). In this proposal we aim to investigate whether inhaled CO can be used therapeutically to suppress the development of lipid-mediated atherosclerosis. Further, we aim to understand the molecular mechanisms underlying this effect.

Funding

POCTI/SAU-MNO/56066/2004 “Fundaçao para a Ciencia e Tecnologia”, Portugal.
Modulation of atherosclerosis by the protective gene heme oxygenase-1: Molecular mechanisms and therapeutic applications

Phillip Morris External Research Program
Anti-atherogenic effect of inhaled carbon monoxide: Assessment of mechanism of action and potential therapeutic applications

Collaborators

Neural Crest Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
Moises Mallo LINK

Research Project

Regulation of T-cell mediated immune responses by the stress responsive gene heme oxygenase-1 (HO-1).

There is now accumulating evidence that expression of HO-1 regulates T cell mediated immunity. Our previous body of work has shown this in the context of the rejection of transplanted organs. We have now extended our studies to test the hypothesis that HO-1 might regulate T cell-mediated autoimmunity involved in the pathogenesis of autoimmune diseases such as diabetes, arthritis or multiple sclerosis (MS). In the case of MS, disease progression is caused by uncontrolled neuroinflammation leading to injury of the central nervous system. In most cases clinical manifestation occur over relatively short periods (relapse episodes) followed by longer periods during which their intensity is decreased (remission episodes). We are testing whether expression of heme oxygenase-1 (HO-1) underlies MS remission using a well-established rodent model of MS, i.e. experimental autoimmune encephalomyelitis (EAE).

Funding

GEMI Fund; AgaLinde Healthcare
Inhaled CO and Multiple Sclerosis. LINK

Collaborators

Lymphocyte Physiology Laboratory, Instituto Gulbenkian de Ciência, Oeiras, Portugal
Jocelyne Demengeot LINK

Research Project

Regulation of the pathogenesis of severe acute malaria by the stress responsive gene heme oxygenase-1 (HO-1).

Up to 60-80% of intra-erythrocyte haemoglobin is degraded in each cycle of erythrocyte infection by Plasmodium, the causative agent of malaria. This leads to the generation of free heme, a potent pro-oxidant that acts in a cytotoxic manner in the parasite as well as in the host. The parasite has developed strategies to cope with heme, polymerizing it into hemozoin. When exposed to free heme host cells, e.g. endothelial cells, up-regulate the expression of heme oxygenase-1 (HO-1). CO generated via heme catabolism by HO-1 acts biologically to limit the deleterious effects of a variety of inflammatory responses. We hypothesized that HO-1 and CO might counter the pathogenesis of cerebral malaria (CM), a syndrome that can develop in the course of malaria infection and lead to neurological disturbances revealed by convulsions, coma and eventually leading to death. We are testing this hypothesis in mice infected with P. berghei ANKA, a well-established experimental model of malaria infection.

Funding

POCTI/SAU-MNO/56066/2004 “Fundação para a Ciência e Tecnologia”, Portugal.
Carbon monoxide generated by heme oxygenase-1 suppresses the pathogenesis of cerebral malaria: mechanism of action”

GEMI Fund AgaLinde Healthcare
Functional Interaction of Nitric and Carbon Monoxide in Suppressing the Pathogenesis of Cerebral Malaria. LINK

Collaborators

Departments of Medicine and Neonatology, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Hungary
Jozsef Balla

Publications

(selected) Updated March (2009).

Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, R. Neal Smith, Coutinho A and Soares, M.P. (2009). Heme Oxygenase-1 Affords Protection Against Non-Cerebral Forms of Severe Malaria Proceedings of the National Academy of Sciences of the United States (in press)

Soares, M.P., Marguti I., Cunha A. and Larsen R. (2009). Immunoregulatory Effects of HO-1: How does it work? Current Opinion in Pharmacology and Toxicology [Epub ahead of print] Link

Cheng C., Noordeloos A.M., Jeney V., Soares, M.P., Moll F., Pasterkamp G., Serruys P.W. and Duckers H.J. (2009). Heme oxygenase 1 determines atherosclerotic lesion progression into a vulnerable plaque Circulation 119(23) :3017-27 Link

Rodrigues l., Filipe J., Seldon M.P., Anrather J., Soares, M.P., Simas J.P (2009). Termination of NF-kB via a gamma herpesvirus that assembles an EC5S ubiquitin ligase EMBO Journal 28(9) :1283-95 Link

Kinderlerer AR, Gregoire IP, Hamdulay SS, Ali F, Steinberg R, Silva G, Ali N, Wang B, Haskard DO, Soares, M.P, Mason JC. . . . (2009). Heme-oxygenase-1 expression enhances vascular endothelial resistance to complement mediated injury through induction of decay-accelerating factor Blood 113, No. 7 :1598-1607 Link

Soares, M.P. and Fritz H. Bach (2009). Heme oxygenase-1: from biology to therapeutic potential Trends in Molecular Medicine 15(2) :50-8 Link

Ferreira A., Balla J., Jeney V., Balla G. and Soares, M.P. (2008). A central role for free heme in the pathogenesis of severe malaria: the missing link ? Journal of Molecular Medicine 86(10) :1097-111 Link

Epiphanio S., Mikolajczak S.A., Gonçalves L.A., Pamplona A., Portugal S., Albuquerque S., Goldberg M., Rebelo S., Anderson D.G., Akinc A., Vornlocher H.P., Kappe S.H.I., Soares, M.P. and Mota M.M. (2008). Induction of HO-1 during Plasmodium liver infection protects infected hepatocytes by modulating the inflammatory response Cell Host & Microbes 3(5) :331-8 Link

Ozaki KS, Marques GM, Nogueira E, Feitoza RQ, Cenedeze MA, Franco MF, Mazzali M, Soares MP, Pacheco-Silva A, Câmara NO (2008). Improved renal function after kidney transplantation is associated with heme oxygenase-1 polymorphism. Clin Transplant 22(5) :609-16 Link

Pamplona, A., Ferreira, A., Balla, J., Jeney, V., Balla, G., Epiphanio, S., Chora, A., Rodrigues, C.D., Cunha-Rodrigues, M., Portugal, S., Soares, M.P.* and Mota, M.M*. NOTE: *Equal contribution. (2007). Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Reviewed in Faculty of 1000 Biology and Reviewed in Faculty of 1000 Medicine Nature Medicine 13 :703-10 Link

Soares M.P. and Bach F.H. (2007). Heme Oxygenase‑1 in organ Transplantation. Frontiers in Bioscience 112 :49432-49451 Link

Chora, A.C., Fontoura, P., Cunha, A., Pais, T.F., Cardoso, S., Ho, P.P., Lee, L.Y., Sobel, R.A, Steinman, L., Soares, M.P. (2007). Heme oxygenase–1 and carbon monoxide suppress autoimmune neuroinflammation. Journal of Clinical Investigation 117 :438-447 Link

Seldon, M.P., Silva, G., Pejanovic, N., Larsen, R., Pombo, Gregoire I., Filipe, J., Anrather, J. and Soares, M.P. (2007). Heme Oxygenase-1 Inhibits the Expression of Adhesion Molecules Associated with Endothelial Cell Activation via Inhibition of Nuclear Factor Kappa B (NF-kB) RelA phosphorylation at Serine2761. The Journal of Immunology 179(11) :7840-51 Link

Silva, G.M., Cunha, A., Grégoire, I.P., Seldon, M.P. and Soares, M. P. (2006). The Antiapoptotic Effect of Heme Oxygenase-1 in Endothelial Cells Involves the Degradation of p38{alpha} MAPK Isoform. Reviewed in Faculty of 1000 Biology The Journal of Immunology 177 :1894-903 Link

Silva, G., Grégoire, I.P., Tokaji L., Chora, A., Seldon, M.P., Marinho Cavalcante, M.C. and Soares, M.P. October, (2005). Heme Oxygenase-1: A protective gene that regulates inflammation and immunity. In “Heme Oxygenase in Biology and Medicine: Emergence of the Products Carbon Monoxide, Iron and the Bile Pigments”. Editors: L.E. Otterbein & Brian S. Zuckerbraun. Link

Bach, F.H., Yamashita, K., Ollinger, R., Akamatsu, Y., McDaid, J., Otterbein, L.E., Wang, H. and Soares, M.P. . October (2005). Heme Oxygenase‑1 (HO‑1) in Transplantation. In “Heme Oxygenase in Biology and Medicine: Emergence of the Products Carbon Monoxide, Iron and the Bile Pigments”. Editors: L.E. Otterbein & Brian S. Zuckerbraun. Link

Soares, M.P., Seldon, M.P., Gregoire, I.P., Vassilevskaia, T., Berberat, P.O., Yu, J., Tsui, T.Y. and Bach, F.H. (2004). Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. The Journal of Immunology 172 :3553–3563 Link

Otterbein, L.E., Haga, M., Zuckerbraun, B.Z., Liu, F., Ruiping Song, R., Usheva, A., Stachulak, C.H., Bodyak, N., Smith, N.R., Cismadia, E., Akamatsu, Y., Flavell R., Billiar, T.R., Tzeng, E., Bach, F.H., Choi, A.M.K. and Soares, M.P. (2003). Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nature Medicine 9 (2) :183-190 Link

Otterbein, L.E.*, Soares, M.P.*, Yamashita, K. and Bach, F.H. NOTE: * Equal contribution (2003). Heme oxygenase-1: unleashing the protective properties of heme. Trend in Immunology 24 8 :449-455 Link

Sato, K., Balla J., Otterbein, L., Smith, N.R., Brouard, S., Lin Y., Czismadia, E., Anrather, J., Sevigny, J., Robson, S.C., Vercellotti, G, Choi, A. M., Bach, F.H. and Soares, M. P. (2001). Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse to rat cardiac transplants Journal of Immunology 166 :4185-4194 Link

Otterbein L., Bach F.H., Alam J., Soares, M.P., Lu H.T., Wysk M., Davis R.J., Flavell R. and Choi A. M. (2000). Carbon monoxide mediates anti-inflammatory effects via the mitogen activated protein kinase pathway. Nature Medicine 6, 4 :422-428 Link

Brouard S., Otterbein L., Anrather J., Tobiasch E., Bach F.H., Choi A.M.K. and Soares, M.P. (2000). Carbon monoxide generated by heme oxygenase-1 suppresses endothelial cell apoptosis via the p38 mitogen activated protein kinase pathway. Journal of Experimental Medicine 192 :1015-1025 Link

Soares, M.P., Lin Y., Sthulmeier K. and Bach F. H. (1999). Accommodation Immunology Today 20 :431-476 Link

Soares, M.P., Lin Y., Anrather, J., Csizmadia, E., Takigami, K, Sato, K., Grey S.T., Colvin, R.B., Choi, A.M., Poss, K.D and Bach, F.H. (1998). Expression of heme-oxygenase-1 (HO-1) can determine cardiac xenograft survival Nature Medicine 4 :91-8 Link

Bach, F.H., Ferran, C., Soares, M., Wrighton C.J., Anrather, J., Winkler, H., Robson, S. C. and Hancock, W.W. (1997). Modification of vascular responses in xenotranplantation inflammation and apoptosis. Nature Medicine 3, 9 :944-948 Link