Excited to present our lab's preprint, exploring how neutrophils - the most abundant white blood cell - are influenced by organismal aging and biological sex! #neutrophils #sexdimorphism #aging
-- a thread --
biorxiv.org/content/10.110…
-- a thread --
biorxiv.org/content/10.110…
This is a new story developed at @USCLeonardDavis and led by Biology of Aging graduate student #RyanLu, which was developed thanks to a collaboration to awesome scientists and friends @KContrepois and #ShalinaTaylor at Stanford. 1/n
Neutrophils are unique because they can use their chromatin as a weapon to fight pathogens in a process termed 'NETosis'. They are extremely short-lived, surviving only ~6h after terminal differentiation, and have thus not been extensively studied throughout organismal aging. 2/n
How their phenotypes differ between female and male animals hasn't been deeply looked at, although more and more work across the field (including from #RoadmapEpigenomics and #ImmGen) has shown that somatic cells, including immune cells, can wildly differ between sexes 3/n
We were curious about how #neutrophils are regulated as a function of organismal aging and biological sex, so we generated a multi-omic resource with transcriptomic, metabolomic and lipidomic profiling from primary mouse bone-marrow neutrophils. 4/n
We find that both aging and sex are associated to molecular differences in neutrophils. Importantly, biological sex associates to the most dramatic differences between profiled individuals, regardless of age. 5/n
The most striking functional changes associated to "omic" remodeling is an overhaul of chromatin metabolism pathways, which seems to lead to increased neutrophil chromatin compaction in male and aged neutrophils, with potential (to be explored) consequences on NETosis. 6/n
We also observe male-bias for increased neutral lipid storage (key energy source and precursor to lipid-based inflammatory mediators), and higher expression of key anti-microbial proteases from primary/azurophilic granules, including neutrophil elastase. 7/n
We use machine-learning to identify candidate regulators of either sex- and age-related omic differences, with Sirt6 (a key longevity regulator with sex-dimorphic impact) emerging as a top predictor for both sex- and age-related gene expression regulation in neutrophils. 8/n
We believe that the dataset and analyses that we present will be a great resource to elucidate why sex or age may present as modifiers of the immune response or of therapeutic efficacy upon infections. 9/n
This also opens up a lot of cool questions: How can #aging impact such short-lived cells - through the aging of progenitors or of the bone-marrow niche? Are sex-differences mediated by sex hormones signaling or chromosome complement? Are these differences plastic? 10/10
