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Deciphering the immune mechanism of increased airway allergic disease in menopausal

Grant number: 23/06670-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): August 01, 2023
Effective date (End): July 31, 2025
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Caroline Marcantonio Ferreira
Grantee:Vitor da Silveira Alves
Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
Associated research grant:21/06751-4 - Deciphering the immune mechanism of increased airway allergic disease in menopause, AP.JP2

Abstract

Asthma is well studied in women of reproductive age, while the menopausal age group has been less investigated. Among women over 50 years of age, menopause can coincide with the onset of asthma or, in women with preexisting asthma, be associated with worsening symptoms. Recently, my laboratory published that reexposure of ovariectomized (OVx) allergic mice to the antigen exacerbates lung inflammation and decreases airway function, but the mechanisms involved are still unclear. Additionally, preventive supplementation, but not therapeutic supplementation, with acetate-producing bacteria is capable of preventing exacerbation of airway inflammation in allergic OVx mice. Short-chain fatty acids (SCFAs), such as acetate, have been implicated in the ability to modulate dendritic cells (DCs) and interfere with the effector function of Th2 cells while increasing regulatory T cell (Treg) levels. However, the mechanisms by which these probiotic bacteria or SCFAs can prevent exacerbation of allergic airway inflammation in OVx mice need to be identified. Recently, it was discovered that allergen-specific resident memory T cells (TRMs) accumulate after exposure to house dust mites (HDM) and can mediate experimental asthma symptoms upon rechallenge. Furthermore, it is known that the transcription factor IRF4+ in conventional type 2 DCs (cDC2) is necessary for the development of Th2 differentiation. In this proposal, we present preliminary data showing that IRF4+ cDC2s are necessary for TRM development. Interestingly, estrogen receptor signaling promotes dendritic cell differentiation through positive regulation of IRF4. Our central hypothesis is that menopause induces exacerbation of preexisting asthma through the induction of IRF4+ cDC2s and Th2-skewed TRM cells, and that SCFAs are capable of suppressing this response. Understanding the mechanisms by which the decline of female sex hormones promotes asthma exacerbation is key to the development of new therapeutic targets. (AU)

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