Issaka Yougbare | University of Toronto (original) (raw)

Papers by Issaka Yougbare

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2014

PLoS ONE, 2012

Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyc... more Systemic lupus erythematosus is a polymorphic and multigenic inflammatory autoimmune disease. Cyclic AMP (cAMP) modulates inflammation and the inhibition of cyclic nucleotide phosphodiesterase type 4 (PDE4), which specifically hydrolyzes cAMP, inhibits TNFa secretion. This study was aimed at investigating the evolution of PDE activity and expression levels during the course of the disease in MRL/lpr lupus-prone mice, and to evaluate in these mice the biological and clinical effects of treatments with pentoxifylline, denbufylline and NCS 613 PDE inhibitors. This study reveals that compared to CBA/ J control mice, kidney PDE4 activity of MRL/lpr mice increases with the disease progression. Furthermore, it showed that the most potent and selective PDE4 inhibitor NCS 613 is also the most effective molecule in decreasing proteinuria and increasing survival rate of MRL/lpr mice. NCS 613 is a potent inhibitor, which is more selective for the PDE4C subtype (IC 50 = 1.4 nM) than the other subtypes (PDE4A, IC 50 = 44 nM; PDE4B, IC 50 = 48 nM; and PDE4D, IC 50 = 14 nM). Interestingly, its affinity for the High Affinity Rolipram Binding Site is relatively low (K i = 148 nM) in comparison to rolipram (K i = 3 nM). Finally, as also observed using MRL/lpr peripheral blood lymphocytes (PBLs), NCS 613 inhibits basal and LPS-induced TNFa secretion from PBLs of lupus patients, suggesting a therapeutic potential of NCS 613 in systemic lupus. This study reveals that PDE4 represent a potential therapeutic target in lupus disease.

Canadian Journal of Physiology and Pharmacology, 2013

Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that evolve... more Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that evolves into progressive and chronic inflammation of multiple joints and organs. Phosphorylation and activation of p38 MAPK, along with the resulting overproduction of interleukin (IL)-1␤, IL-6, and tumour necrosis factor (TNF)-␣ is a hallmark of inflammatory disorders. Here, we investigated the anti-inflammatory pathway modulated by NCS 613, a specific PDE4 inhibitor, on human peripheral blood mononuclear cells (PBMCs) from 5 healthy donors and 12 SLE patients. PDE4 subtypes, p38 MAPK, and IB␣ protein levels were analyzed by Western blot, while NF-B and PDE4B immunostaining was assessed in control and lipopolysaccharide (LPS) -pretreated PBMCs. Proinflammatory cytokines were quantified by ELISA, while IL-1␤ mRNA was resolved by RT-qPCR. NCS 613 treatment decreased PDE4B and upregulated PDE4C in human PBMCs from healthy donors and SLE patients. LPS stimulation increased p38 MAPK phosphorylation and NF-B translocation to the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restored IB␣ detection levels in human PBMCs from both healthy donors and SLE patients. This compound also abolished LPS-induced inflammation in PBMCs by reducing IL-6, IL-8, and TNF-␣ cytokines. NCS 613 is a small molecule displaying anti-inflammatory properties that may provide an alternative or complementary strategy for SLE management. Résumé : Le lupus érythémateux disséminé (LED) est une maladie auto-immune polymorphique et multigénique qui évolue en inflammation progressive et chronique de plusieurs articulations et organes. La phosphorylation et l'activation de p38 MAPK, parallèlement à la surproduction d'IL-1␤, d'IL-6 et de TNF-␣, sont des caractéristiques des maladies inflammatoires. Nous avons examiné la voie anti-inflammtoire modulée par le NCS 613, un inhibiteur spécifique de PDE4, dans les cellules mononucléées du sang périphérique (PBMC) de 5 donneurs sains et 12 patients atteints de LED. Les sous-types de PDE4 ainsi que les niveaux de p38 MAPK et de IB␣ ont été analysés par buvardage Western, alors que la coloration immunologique de NF-B et de PDE4B a été évaluée dans les PBMC contrôles et prétraités au LPS. Les cytokines pro-inflammatoires ont été quantifiées par ELISA, alors que l'ARNm de l'interleukine 1␤ a été quantifié par RT-qPCR. Le traitement au NCS 613 diminuait l'expression de PDE4B et régulait à la hausse PDE4C dans les PBMC humains isolés de donneurs sains et de patients atteints de LED. La stimulation au LPS augmentait la phosphorylation de p38 MAPK et la translocation de NF-B dans le noyau, qui étaient aboli par le traitement au NCS 613. De manière concomitante, le NCS 613 rétablissait les niveaux de IB␣ dans les PBMC humains isolés de donneurs sains et de patients atteints de LED. Ce composé abolissait aussi l'inflammation induite par le LPS dans les PBMC en réduisant le niveau des cytokines IL6, IL8 et TNF␣. Le NCS 613 est une petite molécule qui présente des propriétés anti-inflammatoires et qui peut constituer une stratégie alternative ou complémentaire pour contrôler le LED.

AJP: Lung Cellular and Molecular Physiology, 2011

Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruct... more Chronic inflammation is a hallmark of pulmonary diseases, which leads to lung parenchyma destruction (emphysema) and obstructive bronchiolitis occurring in both chronic obstructive pulmonary disease and asthma. Inflammation is strongly correlated with low intracellular cAMP levels and increase in specific cAMP hydrolyzing activity. The aim of the present study was to investigate the role of the cyclic phosphodiesterase type 4 (PDE4) in human lung and to determine the effects of NCS 613, a new PDE4 inhibitor, on lung inflammation and bronchial hyperresponsiveness. High cAMP-PDE activities were found in the cytosoluble fractions from human lung parenchyma and distal bronchi. PDE4 (rolipram sensitive) represented 40% and 56% of total cAMP-PDE activities in the above-corresponding tissues. Moreover, PDE4A, PDE4B, PDE4C, and PDE4D isoforms were detected in all three subcellular fractions (cytosolic, microsomal, and nuclear) with differential distributions according to specific variants. Pharmacological treatments with NCS 613 significantly decreased PDE4 activity and reduced IκBα degradation in cultured parenchyma, both of which are usually correlated with a lower inflammation status. Moreover, NCS 613 pretreatment potentiated isoproterenol-induced relaxations in human distal bronchi, while reducing TNF-α-induced hyperresponsiveness in cultured bronchi, as assessed in the presence of methacholine, U-46619, or histamine. This reducing effect of NCS 613 on human bronchi hyperresponsiveness triggered by TNF-α was related to a lower expression level of PDE4B and PDE4C, as well as a downregulation of the phosphorylated forms of p38-MAPK, CPI-17, and MYPT-1, which are known to control tone. In conclusion, specific PDE4 inhibitors, such as NCS 613, may represent an alternative and isoform-specific approach toward reducing human lung inflammation and airway overreactivity.

Blood, Jan 2, 2015

Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantib... more Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantibodies targeting platelet surface proteins, most commonly GPIIbIIIa (αIIbβ3 integrin), leading to platelet destruction. Recently, CD8(+) cytotoxic T-lymphocytes (CTL) targeting platelets and megakaryocytes have also been implicated in thrombocytopenia. Since steroids are the most commonly administered therapy for ITP worldwide, we established both active (immunized-splenocyte engraftment) and passive (antibody injection) murine models of steroid treatment. Surprisingly, we found that, in both models, CD8(+) T-cells limited the severity of the thrombocytopenia and were required for an efficacious response to steroid therapy. Conversely, CD8(+) T-cell depletion led to more severe thrombocytopenia, while CD8(+) T-cell transfusion ameliorated thrombocytopenia. CD8(+) T-regulatory cell (Treg) subsets were detected, and interestingly, dexamethasone (DEX) treatment selectively expanded CD8(+) Tr...

Advances in Hematology, 2012

Platelets are small anucleate cells circulating in the blood. It has been recognized for more tha... more Platelets are small anucleate cells circulating in the blood. It has been recognized for more than 100 years that platelet adhesion and aggregation at the site of vascular injury are critical events in hemostasis and thrombosis; however, recent studies demonstrated that, in addition to these classic roles, platelets also have important functions in inflammation and the immune response. Platelets contain many proinflammatory molecules and cytokines (e.g., P-selectin, CD40L, IL-1β, etc.), which support leukocyte trafficking, modulate immunoglobulin class switch, and germinal center formation. Platelets express several functional Toll-like receptors (TLRs), such as TLR-2, TLR-4, and TLR-9, which may potentially link innate immunity with thrombosis. Interestingly, platelets also contain multiple anti-inflammatory molecules and cytokines (e.g., transforming growth factor-β and thrombospondin-1). Emerging evidence also suggests that platelets are involved in lymphatic vessel development by directly interacting with lymphatic endothelial cells through C-type lectin-like receptor 2. Besides the active contributions of platelets to the immune system, platelets are passively targeted in several immune-mediated diseases, such as autoimmune thrombocytopenia, infection-associated thrombocytopenia, and fetal and neonatal alloimmune thrombocytopenia. These data suggest that platelets are important immune cells and may contribute to innate and adaptive immunity under both physiological and pathological conditions.

The Journal of Infection in Developing Countries, 2011

Introduction: The first H5N1 outbreak in Burkina Faso was reported to the World Organization for ... more Introduction: The first H5N1 outbreak in Burkina Faso was reported to the World Organization for Animal Health on 3 April 2006. This study aimed to determine the prevalence of avian influenza virus, infectious bronchitis virus, and Newcastle disease virus among domestic and wild birds in highly pathogenic avian influenza (HPAI) H5N1 outbreaks areas. Methodology: We collected paired tracheal and cloacal swabs from 283 birds including 278 domestic and five wild birds (three vultures, one sparrowhawk and one Western Grey Plantain-eater) in the Central Region (Ouagadougou) and the Western Region (Bobo-Dioulasso and Sokoroni) of Burkina Faso. Total RNA extracted from samples were subjected to reverse transcription and resulting cDNA amplified by PCR using specific primers for detection of Avian Influenza Virus (AIV mainly highly pathogenic H5N1), Infectious Bronchitis Virus (IBV), and Newcastle Disease Virus (NDV) for the first time in Burkina Faso. Results and conclusions: Our results show that 13.8% (39/283) samples were reactive for NDV, and the prevalence of IBV was 3.9% (11/283). None of the 283 birds were co-infected by AIV, IBV and/or NDV in our study areas. The prevalence of influenza A virus was 3.2% (95% CI: 0-6.6) with a 1.7% (95% CI: 0-3.2) prevalence of H5N1 being detected. Positive cases of H5N1 virus were found in two out of three vultures in Ouagadougou, and in three out of 203 local chickens in the Western Region. These results confirm the presence of influenza A H5N1 virus, IBV and NDV in domestic and wild birds in Burkina Faso.

Nature Communications, 2015

Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies ag... more Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current theory suggests that antibody-mediated platelet destruction occurs in the spleen, via macrophages through Fc-FcγR interactions. However, we and others have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often refractory to therapies targeting FcγR pathways. Here, we generate mouse anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of different species. Utilizing these unique mAbs and human ITP plasma, we find that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent platelet activation, sialidase neuraminidase-1 translocation and desialylation. This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell receptors, which is fundamentally different from the classical Fc-FcγR-dependent macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on Fc-independent cytopenias, designating desialylation as a potential diagnostic biomarker and therapeutic target in the treatment of refractory ITP.