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Deciphering the immune mechanism of increased airway allergic disease in menopausal

Grant number: 22/12955-4
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): October 01, 2022
Effective date (End): April 30, 2027
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Caroline Marcantonio Ferreira
Grantee:Antonio Simplicio da Silva Filho
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 has been extensively studied in women of reproductive age, while the menopausal age range has been less studied. Among women over 50 years old, menopause can either coincide with the onset of Asthma or in women with pre-existing Asthma, be associated with the worsening of symptoms. Recently, our lab published findings showing that the re-exposure of ovariectomized (OVx) allergic mice to antigen exacerbates lung inflammation and decreases airway function, how- ever the mechanisms involved are not clear. In addition, preventive but not therapeutic supplemen- tation with the acetate-producing bacterium is able to prevent the increased recall response and airway inflammation in OVx allergic mice. Short-Chain Fatty Acid (SCFA), such as acetate, has been implicated in the impaired ability of Dendritic Cells (DCs) to promote Th2 cell effector func- tion and increase levels of T-regulatory (Tregs) cells. However, the mechanisms by which these probiotics or SCFAs can prevent exacerbation of allergic airway inflammation in OVx mice need to be identified. Recently, allergen-specific resident memory T cells (TRM) have been found to accumulate after HDM exposure and mediate experimental Asthma symptoms upon re-challenge. We show in this proposal preliminary data that the transcription factor, IRF4+, in CD11c+ conven- tional type 2 DC cells (cDC2) is necessary for the development of Th2 differentiation. Interestingly, estrogen receptor signaling promotes dendritic cell differentiation by upregulating IRF4. Our cen- tral hypothesis is that menopause induces exacerbation of pre-existing Asthma through induction of IRF4+ cDC2s and Th2-skewed TRM cells and that SCFA mutes this response. Understanding the mechanisms by which the decline of female sex hormones promotes the worsening of Asthma is key to the development of new targets for therapeutics. (AU)

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