Sex as a biological variable in allergen-induced airway inflammation
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Date
2022-03-23
Authors
Mostafa, Dina
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Abstract
Asthma is a chronic inflammatory respiratory disease with sex-bias in prevalence, severity, and response to therapy. However, allergen-mediated sex-specific immunological and molecular changes in the lungs remain unknown. Thus, the overall objective of this study was to characterize sex-related differences in house dust mite (HDM) allergen-challenged mouse, using two different strains of mice, and examine selected proteins in bronchoalveolar lavage fluid (BALF) from atopic human participants.
Female and male mice were challenged (intranasal) with HDM, from two different genetic backgrounds BALB/c and C57BL/6NJ. Outcomes measured included leukocyte accumulation in the BALF, the abundance of a panel of 29 cytokines in BALF and lung tissues, and HDM-specific antibodies (IgE) in serum. Overall, the results showed that female BALB/c mice predominantly mount a Th17-biased response to HDM challenge compared to males, whereas C57BL/6NJ female mice display a mixed Th1/Th2-skewed response. Males of both strains show a Th2-slewed response compared to females. This highlights the interplay between genetic variability and sex difference in airway inflammation and the importance of taking the mice strain into consideration when interpreting results.
Previous studies using proteomics approaches have characterized allergen-induced changes in secreted proteins (secretome) in the lung of female BALB/c mice, and in human participants. Here, we performed a comparative assessment of these published datasets and identified a panel of 19 proteins enhanced in response to allergen, in both mice and humans. We examined sex-related differences in the abundance of the top 10 proteins selected from this 19-protein panel. We demonstrated that females have significantly higher levels of eosinophil peroxidase (EPX) in both mice and human BALF, in response to allergen, thus identifying a female-specific biomarker for allergic asthma. We also showed distinct differences between species; for example, allergen-mediated increase in S100A8 and S100A9 were higher in females compared to males in mice BALF, whereas higher in males in humans.
In conclusion, the findings in study will provide the foundation for future work that recognizes the importance of integrating sex as a biological variable for asthma research, and will enable the translation of novel biomarkers from animal models to human studies in a sex-dependent manner.
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Keywords
Sex differences, Airway Inflammation, Mice strain differences