New study sheds light on sex differences in allergic airway inflammation

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In a recently published study, Dr Physiological Genomics, A group of researchers explored how sex hormones and chromosome four-core genotype (FCG) influence allergic inflammation and gene expression in mice exposed to house dust mite (HDM).

Study: transcriptomics analysis of allergen-induced-inflammatory gene expression in a four-core genotype mouse model.  Image credit: SciePro/Shutterstock.com
Study: Transcriptomics analysis of allergen-induced inflammatory gene expression in a four-core genotype mouse model. Image credit: SciePro/Shutterstock.com

Background

Asthma, affecting more than 300 million people worldwide, shows widely significant gender differences, more so in male children and female adults, indicating the influence of sex hormones. Studies link the hypothalamic-gonadal-pituitary axis to lung function and immunity, and genetic factors, particularly X chromosome variations, contribute to sex-specific asthma characteristics.

Infiltrating inflammatory lung cells, environmental allergens such as HDM, particularly Dermatophagoides species, cause airway inflammation. Although sex- and strain-specific responses to HDM have been documented, the precise influence of sex chromosomes and hormones on asthma remains unclear, requiring further research into these complex interactions for better asthma management.

About the study

In the present study, FCG mice with C57BL/6J background were obtained from Jackson Laboratories and bred in house. These mice genotyped as XX-male (XXM), XX-female (XXF), XY-male (XYM), or XY-female (XYF) using genomic polymerase chain reaction (PCR) were grouped into control and experimental sets. 8–10 weeks of age followed National Institutes of Health guidelines and Bloomington Institutional Animal Care and Use Committee approval.

The experimental group received intranasal instillation of an HDM solution derived from Dermatophagoides species five times a week for five weeks. The control group was similarly administered phosphate-buffered saline (PBS). This procedure was performed under post-light anesthesia using pipette tips.

Lung lavage fluid was collected for cell counts, while lung tissues were used for ribonucleic acid (RNA) extraction and gene expression analysis, involving tempo-seq assays and data processing with GraphPad Prism and DESeq2 in R.

Finally, QIAGEN Ingenuity Pathway Analysis was used to examine networks of differentially expressed genes, focusing specifically on canonical pathways related to asthma and lung inflammation.

Results of the study

In the study, FCG mice were exposed to intranasal PBS or HDM for five weeks. The analysis indicated a trend towards increased neutrophil and eosinophil numbers in the HDM group, particularly in the XYF genotype, although these increases were not statistically significant. This pattern was also observed to a lesser extent in XXF and XXM genotypes. When comparing genotypes, no significant changes in eosinophil and neutrophil counts were observed between animals exposed to PBS versus HDM.

The study also conducted a thorough gene expression analysis using Tempo-Seq on lung tissue from control and HDM-exposed mice. The aim was to identify differentially expressed genes (DEGs) and most DEGs were upregulated across all genotypes in response to HDM, XXM mice being an exception. Significant DEGs in the study are presented in various figures and tables. Importantly, the response varied between genotypes, with different numbers of upregulated and downregulated genes observed.

Further subdivision of animals based on sex chromosomes and gonads revealed more up-regulated genes in XX mice compared to XY mice when challenged with HDM. However, no significant gene differences were observed between XX and XY HDM-challenged mice. In contrast, a significant number of genes were differentially expressed between female and male HDM-challenged groups, with a mixture of upregulated and downregulated genes.

Ingenuity Pathway Analysis (IPA) provides insight into the top upstream regulators and canonical pathways involved in the response to HDM challenge. Notably, different pathways were enriched in different genotypic groups. For example, the glucocorticoid receptor signaling pathway was prominent in the XYM and XXF groups, while farnesoid

The study also found that inflammatory responses and immunological diseases were common in all groups when comparing animals with the same sex chromosomes or hormones.

In terms of molecular and cellular function, differences based on sex chromosomes and gonads have been observed. For example, DEGs in the XXM HDM-challenged group were mostly associated with the proliferation of various cell lines, including lymphocytes and gonad cells. In contrast, most DEGs in the XXF HDM-challenged group, known to reduce inflammation, were upregulated.

The XYM group presented DEGs affecting chronic inflammation, and the DEGs in the group with female chromosomes (XXF vs. XXM) were related to respiratory inflammatory processes.

Finally, cellular functions such as cell death, survival, and development including the female gonad were mainly associated with identified DEGs. In contrast, in the group with male gonads, most DEGs known to increase inflammation were downregulated.

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