Role of short-chain fatty acids in NLRP3 activation in severe asthma model

• Grant number: 17/19020-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: March 01, 2018
• End date: June 30, 2019
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Flávio Aimbire Soares de Carvalho
• Grantee: Barbara Silva Tagé de Souza
• Host Institution: Instituto de Ciência e Tecnologia (ICT). Universidade Federal de São Paulo (UNIFESP). Campus São José dos Campos. São José dos Campos , SP, Brazil

Abstract

Asthma is considered a syndrome with high morbidity levels that reaches 300 million people in the world today. Pharmacological treatment for asthma control has side effects that reduce the quality of life of the patients. In addition, asthma presents a high cost to public health due to hospitalizations and the use of medications. Because asthma involves multiple phenotypes, it is extremely difficult to delineate the profiles involved in asthma. The phenotype of allergic asthma is the most common and that of neutrophilic asthma is difficult to treat pharmacologically. In general, asthma involves bronchial hyperreactivity, increasing secretion of mucus, recruitment of inflammatory cells, activation of the immune system, and inflammation of the airways and lungs resulting from the exaggerated response to allergens. In asthma, the first cells in the lungs to come in contact with the allergen are the macrophages resident in the alveoli and the dendritic cells; both are sentinels that trigger the inflammatory process. The exacerbation of the inflammatory response in asthma is associated with the formation of protein complexes called inflamassomes, with NLRP3 being the most studied. This complex, when activated by the recognition of damages or pathogens, acts as an activation platform for caspase-1. Once active, caspase-1 induces an inflammatory response by converting the inactive cytokines IL-1² and IL-18 into active cytokines, in addition to inducing the cell death process called pyroptosis. In this way, the inflamassome contributes to the containment of pathogens and the tissue repair. On the other hand, inflamassome are also involved with the aggravation of several inflammatory diseases, among them, asthma. Considering the high morbidity rate of asthma and the high cost of treatment for public health, research on therapies capable of modulating the inflammatory response in an effective manner and with few side effects is important. In this sense, short chain fatty acids (SCFA) have been shown to be efficient in controlling the migration of inflammatory cells to inflamed sites and reduced the production of proinflammatory cytokines, such as TNF, IL-6 and IL-1² in different experimental models of inflammation and in patients with chronic inflammatory diseases. Therefore, SCFA can be seen as a strategy of therapeutic relevance in the control of exacerbated inflammatory processes as observed in asthma. Therefore, the present project aims to investigate the role of SCFAs in the activation of NLRP3 in alveolar macrophages of mice submitted to neutrophilic asthma induced by the mite. (AU)