Bonney, E. A. | bioRxiv Science

bioRxiv2025

Single cell analysis of ovarian immune cells during homeostasis and hormonal flux reveals dynamic changes in NK and B cell populations in the periovulatory phase

The mammalian ovary is the dynamic end-organ of the hypothalamic pituitary ovarian axis. In this coordinated system, ovarian cells undergo continuous cycles of apoptosis, proliferation, and differentiation. These changes parallel fluctuations in ovarian hormones such as estradiol (E2); however, the ovarian immune microenvironment during high-E2 and low-E2 states is not fully understood. We induced a high-E2 state in the mouse ovary by stimulation via gonadotropin treatment. Single-cell RNA sequencing and flow cytometry analysis of ovarian leukocytes revealed abundant mature NK cells, B1 and B2 cells, CD8+ T cells, CD4+ T cells, mature CD4-CD8-T cells, T regulatory cells, and distinct myeloid subsets, including Trem2+ and Apoe+ macrophages. In vivo labeling of circulating cells determined that the vast majority of ovarian leukocytes were tissue-resident. Following gonadotropin treatment, the frequency of NK cells increased two-fold, while B1 cell frequency was reduced by half. Consistently, flow cytometric analysis revealed an increase in mature CD11b+ NK cells following gonadotropin treatment. Gonadotropin treatment also increased cell-cell signaling by myeloid cells at the expense of NK cells. Our findings reveal a diverse resident immune landscape in the ovary that responds robustly to hormonal changes. These findings have implications for a role for immune cells in ovarian physiology and functional dysregulation.

immunology↗

bioRxiv2024

Inflammation promotes aging-associated oncogenesis in the lung.

BackgroundLung cancer is the leading cause of cancer death in the world. While cigarette smoking is the major preventable factor for cancers in general and lung cancer in particular, old age is also a major risk factor. Aging-related chronic, low-level inflammation, termed inflammaging, has been widely documented; however, it remains unclear how inflammaging contributes to increased lung cancer incidence. AimTo establish connections between aging-associated changes in the lungs and cancer risk. MethodsWe analyzed public databases of gene expression for normal and cancerous human lungs and used mouse models to understand which changes were dependent on inflammation, as well as to assess the impact on oncogenesis. ResultsAnalyses of GTEx and TCGA databases comparing gene expression profiles from normal lungs, lung adenocarcinoma, lung squamous cell carcinoma of subjects across age groups revealed upregulated pathways such as inflammatory response, TNFA signaling via NF{kappa}B, and interferon-gamma response. Similar pathways were identified comparing the gene expression profiles of young and old mouse lungs. Transgenic expression of alpha 1 antitrypsin (AAT) partially reverses increases in markers of aging-associated inflammation and immune deregulation. Using an orthotopic model of lung cancer using cells derived from EML4-ALK fusion-induced adenomas, we demonstrated an increased tumor outgrowth in lungs of old mice while NLRP3 knockout in old mice decreased tumor volumes, suggesting that inflammation contributes to increased lung cancer development in aging organisms. ConclusionsThese studies reveal how expression of an anti-inflammatory mediator (AAT) can reduce some but not all aging-associated changes in mRNA and protein expression in the lungs. We further show that aging is associated with increased tumor outgrowth in the lungs, which may relate to an increased inflammatory microenvironment.

cancer biology↗