Myeloid Heme Oxygenase-1 Regulates the Acute Inflammatory Response to Zymosan in the Mouse Air Pouch

[EN] Heme oxygenase-1 (HO-1) is induced by many stimuli to modulate the activation and function of different cell types during innate immune responses. Although HO-1 has shown anti-inflammatory effects in different systems, there are few data on the contribution of myeloid HO-1 and its role in inflammatory processes is not well understood. To address this point, we have used HO-1(M-KO) mice with myeloid-restricted deletion of HO-1 to specifically investigate its influence on the acute inflammatory response to zymosan in vivo. In the mouse air pouch model, we have shown an exacerbated inflammation in HO-1(M-KO) mice with increased neutrophil infiltration accompanied by high levels of inflammatory mediators such as interleukin-1 beta, tumor necrosis factor-a, and prostaglandin E-2. The expression of the degradative enzyme matrix metalloproteinase-3 (MMP-3) was also enhanced. In addition, we observed higher levels of serum MMP-3 in HO-1(M-KO) mice compared with control mice, suggesting the presence of systemic inflammation. Altogether, these findings demonstrate that myeloid HO-1 plays an anti-inflammatory role in the acute response to zymosan in vivo and suggest the interest of this target to regulate inflammatory processes.This work has been funded by grants SAF2010-22048, SAF2013-4874R (MINECO, FEDER), PROMETEO/2010/047, and PROMETEOII/2014/071 (Generalitat Valenciana).Brines, R.; Catalán, L.; Alcaraz Tormo, MJ.; Ferrandiz Manglano, ML. (2018). Myeloid Heme Oxygenase-1 Regulates the Acute Inflammatory Response to Zymosan in the Mouse Air Pouch. Oxidative Medicine and Cellular Longevity. 2018. https://doi.org/10.1155/2018/5053091S2018Grochot-Przeczek, A., Dulak, J., & Jozkowicz, A. (2011). Haem oxygenase-1: non-canonical roles in physiology and pathology. Clinical Science, 122(3), 93-103. doi:10.1042/cs20110147Busserolles, J., Megías, J., Terencio, M. 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Heme oxygenase-1 mediates protective effects on inflammatory, catabolic and senescence responses induced by interleukin-1β in osteoarthritic osteoblasts. Biochemical Pharmacology, 83(3), 395-405. doi:10.1016/j.bcp.2011.11.024Gozzelino, R., Jeney, V., & Soares, M. P. (2010). Mechanisms of Cell Protection by Heme Oxygenase-1. Annual Review of Pharmacology and Toxicology, 50(1), 323-354. doi:10.1146/annurev.pharmtox.010909.105600Naito, Y., Takagi, T., & Higashimura, Y. (2014). Heme oxygenase-1 and anti-inflammatory M2 macrophages. Archives of Biochemistry and Biophysics, 564, 83-88. doi:10.1016/j.abb.2014.09.005Orozco, L. D., Kapturczak, M. H., Barajas, B., Wang, X., Weinstein, M. M., Wong, J., … Araujo, J. A. (2007). Heme Oxygenase-1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis. Circulation Research, 100(12), 1703-1711. doi:10.1161/circresaha.107.151720Perrella, M., & Yet, S.-F. (2003). Role of Heme Oxygenase-1 in Cardiovascular Function. 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Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury. Scientific Reports, 7(1). doi:10.1038/s41598-017-00220-wJais, A., Einwallner, E., Sharif, O., Gossens, K., Lu, T. T.-H., Soyal, S. M., … Esterbauer, H. (2014). Heme Oxygenase-1 Drives Metaflammation and Insulin Resistance in Mouse and Man. Cell, 158(1), 25-40. doi:10.1016/j.cell.2014.04.043Konrad, F. M., Knausberg, U., Höne, R., Ngamsri, K.-C., & Reutershan, J. (2015). Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation. Mucosal Immunology, 9(1), 98-111. doi:10.1038/mi.2015.39Underhill, D. M. (2003). Macrophage recognition of zymosan particles. Journal of Endotoxin Research, 9(3), 176-180. doi:10.1177/09680519030090030601MORONEY, M.-A., ALCARAZ, M. J., FORDER, R. A., CAREY, F., & HOULT, J. R. S. (1988). 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Nrf2 as a therapeutic target for rheumatic diseases

[EN] Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of cellular protective processes. Rheumatic diseases are chronic conditions characterized by inflammation, pain, tissue damage and limitations in function. Main examples are rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis and osteoporosis. Their high prevalence constitutes a major health problem with an important social and economic impact. A wide range of evidence indicates that Nrf2 may control different mechanisms involved in the physiopathology of rheumatic conditions. Therefore, the appropriate expression and balance of Nrf2 is necessary for regulation of oxidative stress, inflammation, immune responses, and cartilage and bone metabolism. Numerous studies have demonstrated that Nrf2 deficiency aggravates the disease in experimental models while Nrf2 activation results in immunoregulatory and anti-inflammatory effects. These reports reinforce the increasing interest in the pharmacologic regulation of Nrf2 and its potential applications. Nevertheless, a majority of Nrf2 inducers are electrophilic molecules which may present off-target effects. In recent years, novel strategies have been sought to modulate the Nrf2 pathway which has emerged as a therapeutic target in rheumatic conditions.This work has been funded by grant SAF2017-85806-R (MINECO, FEDER, Spain).Ferrandiz Manglano, ML.; Nacher-Juan, J.; Alcaraz Tormo, MJ. (2018). Nrf2 as a therapeutic target for rheumatic diseases. Biochemical Pharmacology. 152:338-346. https://doi.org/10.1016/j.bcp.2018.04.010S33834615

Osteostatin Inhibits Collagen-Induced Arthritis by Regulation of Immune Activation, Pro-Inflammatory Cytokines, and Osteoclastogenesis

[EN] In chronic inflammatory joint diseases, such as rheumatoid arthritis, there is an important bone loss. Parathyroid hormone-related protein (PTHrP) and related peptides have shown osteoinductive properties in bone regeneration models, but there are no data on inflammatory joint destruction. We have investigated whether the PTHrP (107-111) C-terminal peptide (osteostatin) could control the development of collagen-induced arthritis in mice. Administration of osteostatin (80 or 120 mu g/kg s.c.) after the onset of disease decreased the severity of arthritis as well as cartilage and bone degradation. This peptide reduced serum IgG2a levels as well as T cell activation, with the downregulation of ROR gamma t+CD4+ T cells and upregulation of FoxP3+CD8+ T cells in lymph nodes. The levels of key cytokines, such as interleukin(IL)-1 beta, IL-2, IL-6, IL-17, and tumor necrosis factor-alpha in mice paws were decreased by osteostatin treatment, whereas IL-10 was enhanced. Bone protection was related to reductions in receptor activator of nuclear factor-kappa B ligand, Dickkopf-related protein 1, and joint osteoclast area. Osteostatin improves arthritis and controls bone loss by inhibiting immune activation, pro-inflammatory cytokines, and osteoclastogenesis. Our results support the interest of osteostatin for the treatment of inflammatory joint conditions.This work has been funded by grant SAF2017-85806-R (Ministerio de Ciencia, Innovación y Universidades, Spain, FEDER). J. Nácher-Juan thanks Universitat de València, Spain, for a PhD fellowship (INV18-01-13-01).Nacher-Juan, J.; Terencio Silvestre, MC.; Alcaraz Tormo, MJ.; Ferrandiz Manglano, ML. (2019). Osteostatin Inhibits Collagen-Induced Arthritis by Regulation of Immune Activation, Pro-Inflammatory Cytokines, and Osteoclastogenesis. International Journal of Molecular Sciences. 20(16):1-18. https://doi.org/10.3390/ijms20163845S1182016De Gortázar, A. R., Alonso, V., Alvarez-Arroyo, M. V., & Esbrit, P. (2006). Transient Exposure to PTHrP (107-139) Exerts Anabolic Effects through Vascular Endothelial Growth Factor Receptor 2 in Human Osteoblastic Cells In Vitro. Calcified Tissue International, 79(5), 360-369. doi:10.1007/s00223-006-0099-yTrejo, C. G., Lozano, D., Manzano, M., Doadrio, J. C., Salinas, A. J., Dapía, S., … Buján, J. (2010). The osteoinductive properties of mesoporous silicate coated with osteostatin in a rabbit femur cavity defect model. Biomaterials, 31(33), 8564-8573. doi:10.1016/j.biomaterials.2010.07.103Fenton, A. J., Martin, T. J., & Nicholson, G. C. (2009). Carboxyl-terminal parathyroid hormone-related protein inhibits bone resorption by isolated chicken osteoclasts. Journal of Bone and Mineral Research, 9(4), 515-519. doi:10.1002/jbmr.5650090411Firestein, G. S., & McInnes, I. B. (2017). Immunopathogenesis of Rheumatoid Arthritis. Immunity, 46(2), 183-196. doi:10.1016/j.immuni.2017.02.006Scholtysek, C., Kronke, G., & Schett, G. (2012). Inflammation-Associated Changes in Bone Homeostasis. Inflammation & Allergy-Drug Targets, 11(3), 188-195. doi:10.2174/187152812800392706Szentpétery, Á., Horváth, Á., Gulyás, K., Pethö, Z., Bhattoa, H. P., Szántó, S., … Szekanecz, Z. (2017). Effects of targeted therapies on the bone in arthritides. Autoimmunity Reviews, 16(3), 313-320. doi:10.1016/j.autrev.2017.01.014Kohno, H., Shigeno, C., Kasai, R., Akiyama, H., Iida, H., Tsuboyama, T., … Nakamura, T. (1997). Synovial Fluids from Patients with Osteoarthritis and Rheumatoid Arthritis Contain High Levels of Parathyroid Hormone-Related Peptide. Journal of Bone and Mineral Research, 12(5), 847-854. doi:10.1359/jbmr.1997.12.5.847Fischer, J., Dickhut, A., Rickert, M., & Richter, W. (2010). Human articular chondrocytes secrete parathyroid hormone-related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis. Arthritis & Rheumatism, 62(9), 2696-2706. doi:10.1002/art.27565Chen, X., Macica, C. M., Nasiri, A., & Broadus, A. E. (2008). Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis & Rheumatism, 58(12), 3788-3797. doi:10.1002/art.23985HORIUCHI, T., YOSHIDA, T., KOSHIHARA, Y., SAKAMOTO, H., KANAI, H., YAMAMOTO, S., & ITO, H. (1999). The Increase of Parathyroid Hormone-Related Peptide and Cytokine Levels in Synovial Fluid of Elderly Rheumatoid Arthritis and Osteoarthritis. Endocrine Journal, 46(5), 643-649. doi:10.1507/endocrj.46.643Platas, J., Guillén, M. I., Gomar, F., Castejón, M. A., Esbrit, P., & Alcaraz, M. J. (2016). Anti-senescence and Anti-inflammatory Effects of the C-terminal Moiety of PTHrP Peptides in OA Osteoblasts. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw100. doi:10.1093/gerona/glw100Myers, L. K., Rosloniec, E. F., Cremer, M. A., & Kang, A. H. (1997). Collagen-induced arthritis, an animal model of autoimmunity. 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Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles

[EN] Acute inflammation is a protective response of the body to harmful stimuli, such as pathogens or damaged cells. However, dysregulated inflammation can cause secondary damage and could thus contribute to the pathophysiology of many diseases. Inflammasomes, the macromolecular complexes responsible for caspase-1 activation, have emerged as key regulators of immune and inflammatory responses. Therefore, modulation of inflammasome activity has become an important therapeutic approach. Here we describe the design of a smart nanodevice that takes advantage of the passive targeting of nanoparticles to macrophages and enhances the therapeutic effect of caspase-1 inhibitor VX-765 in vivo. The functional hybrid systems consisted of MCM-41-based nanoparticles loaded with anti-inflammatory drug VX-765 (S2-P) and capped with poly-L-lysine, which acts as a molecular gate. S2-P activity has been evaluated in cellular and in vivo models of inflammation. The results indicated the potential advantage of using nanodevices to treat inflammatory diseases. (C) 2017 Elsevier B.V. All rights reserved.The authors wish to express their gratitude to the Spanish government (Projects MAT2015-64139-C4-1-R and SAF2014-52614-R (MINECO/FEDER)) and the Generalitat Valencia (Projects PROMETEOII/2014/061 and PROMETEOII/2014/047) for support. A.G-F. is grateful to the Spanish government for an FPU grant.García-Fernández, A.; García-Laínez, G.; Ferrandiz Manglano, ML.; Aznar, E.; Sancenón Galarza, F.; Alcaraz, MJ.; Murguía, JR.... (2017). Targeting inflammasome by the inhibition of caspase-1 activity using capped mesoporous silica nanoparticles. Journal of Controlled Release. 248:60-70. https://doi.org/10.1016/j.jconrel.2017.01.002S607024