Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis

© 2010 Cascão et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by sustained synovitis. Recently, several studies have proposed neutrophils and Th17 cells as key players in the onset and perpetuation of this disease. The main goal of this work was to determine whether cytokines driving neutrophil and Th17 activation are dysregulated in very early rheumatoid arthritis patients with less than 6 weeks of disease duration and before treatment (VERA). Methods: Cytokines related to neutrophil and Th17 activation were quantified in the serum of VERA and established RA patients and compared with other very early arthritis (VEA) and healthy controls. Synovial fluid (SF) from RA and osteoarthritis (OA) patients was also analyzed. Results: VERA patients had increased serum levels of cytokines promoting Th17 polarization (IL-1b and IL-6), as well as IL-8 and Th17-derived cytokines (IL-17A and IL-22) known to induce neutrophil-mediated inflammation. In established RA this pattern is more evident within the SF. Early treatment with methotrexate or corticosteroids led to clinical improvement but without an impact on the cytokine pattern. Conclusions: VERA patients already display increased levels of cytokines related with Th17 polarization and neutrophil recruitment and activation, a dysregulation also found in SF of established RA. 0 Thus, our data suggest that a cytokine-milieu favoring Th17 and neutrophil activity is an early event in RA pathogenesis.This work was supported by a grant from Sociedade Portuguesa de Reumatologia/Schering-Plough 2005. RAM and RC were funded by Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/30247/2006 and SFRH/BD/40513/2007, respectively. MMS-C was funded by Marie Curie Intra-European Fellowship PERG-2008-239422 and a EULAR Young Investigator Award

Macro- and micro-geographic variation of short-beaked common dolphin’s whistles in the Mediterranean Sea and Atlantic Ocean

Author Posting. © The Author(s), 20113. This is the author's version of the work. It is posted here by permission of Taylor & Francis for personal use, not for redistribution. The definitive version was published in Ethology Ecology & Evolution 26 (2014): 392-404, doi:10.1080/03949370.2013.851122.Genetic studies have shown that there are small but significant differences between the short-beaked common dolphin populations in the Atlantic Ocean and those in the Mediterranean Sea. The short-beaked common dolphin is a highly vocal species with a wide sound production repertoire including whistles. Whistles are continuous, narrowband, frequency-modulated signals that can show geographic variation in dolphin species. This study tests whether the differences, highlighted by genetic studies, are recognisable in the acoustic features of short-beaked common dolphin’s whistles in the two adjacent areas of the Atlantic Ocean and the Mediterranean Sea. From a selected sample of good quality whistles (514 recorded in the Atlantic and 193 in the Mediterranean) 10 parameters of duration, frequency and frequency modulation were measured. Comparing data among basins, differences were found for duration and all frequency parameters except for minimum frequency. Modulation parameters showed the highest coefficient of variation. Through discriminant analysis we correctly assigned 75.7% of sounds to their basins. Furthermore, micro-geographic analysis revealed similarity between the sounds recorded around the Azores and the Canary archipelagos and between the Bay of Biscay and the Mediterranean Sea. Results are in agreement with the hypothesis proposed by previous genetic studies that two distinct populations are present, still supposing a gene flow between the basins. This study is the first to compare shortbeaked common dolphin’s whistles of the Atlantic Ocean and the Mediterranean areas.Data collection and processing in the Azores was conducted under projects POCTI/BSE/38991/01, PTDC/MAR/74071/2006 and M2.1.2/F/012/2011, supported by FCT (Fundação para a Ciência e a Tecnologia) and DRCTC/SRCTE (Secretaria Regional de Ciência, Tecnologia e Equipamentos), FEDER funds, the Competitiveness Factors Operational (COMPETE), QREN European Social Fund and Proconvergencia Açores Program. We acknowledge funds provided by FCT to LARSyS Associated Laboratory & IMAR-University of the Azores/ the Thematic Area E of the Strategic Project (OE & Compete) and by the DRCTC – Government of the Azores pluriannual funding. M.A. Silva was supported by an FCT postdoctoral grant (SFRH/ BPD/29841/2006). I. Cascão and R. Prieto were supported by FCT doctoral grants (SFRH/BD/ 41192/2007 and SFRH/BD/32520/2006, respectively) and R. Prieto by a research grant from the Azores Regional Fund for Science and Technology (M3.1.5/F/115/2012). Data collection by SECAC (Society for the Study of Cetaceans in the Canary Archipelago) was funded by the U.E. LIFE programme – project LIFE INDEMARES (LIFE 07/NAT/E/000732)- and the Fundación Biodiversidad, under the Spanish Ministry of Environment, Rural and Marine Affairs (project ZEC-TURSIOPS).2014-11-0

Decrease of CD68 Synovial Macrophages in Celastrol Treated Arthritic Rats

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by cellular infiltration into the joints, hyperproliferation of synovial cells and bone damage. Available treatments for RA only induce remission in around 30% of the patients, have important adverse effects and its use is limited by their high cost. Therefore, compounds that can control arthritis, with an acceptable safety profile and low production costs are still an unmet need. We have shown, in vitro, that celastrol inhibits both IL-1β and TNF, which play an important role in RA, and, in vivo, that celastrol has significant anti-inflammatory properties. Our main goal in this work was to test the effect of celastrol in the number of sublining CD68 macrophages (a biomarker of therapeutic response for novel RA treatments) and on the overall synovial tissue cellularity and joint structure in the adjuvant-induced rat model of arthritis (AIA).FCT fellowship: (SFRH/BPD/92860/2013)

Chronic arthritis leads to disturbances in the bone collagen network

Peer reviewe

Oral tolerance inhibits pulmonary eosinophilia in a cockroach allergen induced model of asthma: a randomized laboratory study

<p>Abstract</p> <p>Background</p> <p>Antigen desensitization through oral tolerance is becoming an increasingly attractive treatment option for allergic diseases. However, the mechanism(s) by which tolerization is achieved remain poorly defined. In this study we endeavored to induce oral tolerance to cockroach allergen (CRA: a complex mixture of insect components) in order to ameliorate asthma-like, allergic pulmonary inflammation.</p> <p>Methods</p> <p>We compared the pulmonary inflammation of mice which had received four CRA feedings prior to intratracheal allergen sensitization and challenge to mice fed PBS on the same time course. Respiratory parameters were assessed by whole body unrestrained plethysmography and mechanical ventilation with forced oscillation. Bronchoalveolar lavage fluid (BAL) and lung homogenate (LH) were assessed for cytokines and chemokines by ELISA. BAL inflammatory cells were also collected and examined by light microscopy.</p> <p>Results</p> <p>CRA feeding prior to allergen sensitization and challenge led to a significant improvement in respiratory health. Airways hyperreactivity measured indirectly via enhanced pause (Penh) was meaningfully reduced in the CRA-fed mice compared to the PBS fed mice (2.3 ± 0.4 vs 3.9 ± 0.6; p = 0.03). Directly measured airways resistance confirmed this trend when comparing the CRA-fed to the PBS-fed animals (2.97 ± 0.98 vs 4.95 ± 1.41). This effect was not due to reduced traditional inflammatory cell chemotactic factors, Th2 or other cytokines and chemokines. The mechanism of improved respiratory health in the tolerized mice was due to significantly reduced eosinophil numbers in the bronchoalveolar lavage fluid (43300 ± 11445 vs 158786 ± 38908; p = 0.007) and eosinophil specific peroxidase activity in the lung homogenate (0.59 ± 0.13 vs 1.19 ± 0.19; p = 0.017). The decreased eosinophilia was likely the result of increased IL-10 in the lung homogenate of the tolerized mice (6320 ± 354 ng/mL vs 5190 ± 404 ng/mL, p = 0.02).</p> <p>Conclusion</p> <p>Our results show that oral tolerization to CRA can improve the respiratory health of experimental mice in a CRA-induced model of asthma-like pulmonary inflammation by reducing pulmonary eosinophilia.</p

Mer receptor tyrosine kinase mediates both tethering and phagocytosis of apoptotic cells

Billions of inflammatory leukocytes die and are phagocytically cleared each day. This regular renewal facilitates the normal termination of inflammatory responses, suppressing pro-inflammatory mediators and inducing their anti-inflammatory counterparts. Here we investigate the role of the receptor tyrosine kinase (RTK) Mer and its ligands Protein S and Gas6 in the initial recognition and capture of apoptotic cells (ACs) by macrophages. We demonstrate extremely rapid binding kinetics of both ligands to phosphatidylserine (PtdSer)-displaying ACs, and show that ACs can be co-opsonized with multiple PtdSer opsonins. We further show that macrophage phagocytosis of ACs opsonized with Mer ligands can occur independently of a requirement for αV integrins. Finally, we demonstrate a novel role for Mer in the tethering of ACs to the macrophage surface, and show that Mer-mediated tethering and subsequent AC engulfment can be distinguished by their requirement for Mer kinase activity. Our results identify Mer as a receptor uniquely capable of both tethering ACs to the macrophage surface and driving their subsequent internalization