Blood and adipose-resident eosinophils are defined by distinct transcriptional profiles

Abstract

Eosinophils are granular leukocytes of the innate immune system that play important functions in host defense. Inappropriate activation of eosinophils can occur in pathologies such as asthma and esophagitis. However, eosinophils also reside within adipose tissue, where they play homeostatic roles and are important in the activation of thermogenic beige fat. Here we performed bulk RNA sequencing in mouse adipose tissue-resident eosinophils isolated from both subcutaneous and gonadal depots, for the first time, and compared gene expression to blood eosinophils. We found a predominantly conserved transcriptional landscape in eosinophils between adipose depots that is distinct from blood eosinophils in circulation. Through exploration of differentially expressed transcription factors and transcription factors with binding sites enriched in adipose-resident eosinophil genes, we identified KLF, CEBP, and Fos/Jun family members that may drive functional specialization of eosinophils in adipose tissue. These findings increase our understanding of tissue-specific eosinophil heterogeneity, with implications for targeting eosinophil function to treat metabolic disorders such as obesity.

Linking adipose tissue eosinophils, IL-4, and leptin in human obesity and insulin resistance

“…Functional assays on circulating EOS may not reflect the activation status of these cells in AT. Genomic evaluation, such as completed with large numbers of rodent EOS ( 50 ), would provide substantial data from our cohorts. However, the volatile nature of human EOS and overall small number of these cells isolated from AT make it difficult to perform downstream transcriptomic analysis ( 27 ).…”

Eosinophils in obesity and obesity-associated disorders

“…Upon infiltrating the AT, eosinophils undergo phenotypic and functional specialization driven by the AT niche itself, promoting expression of TF such as Kruppel-like Factor 3 (KLF3), CEBPs, Fos/Jun in eosinophils [ 19 , 30 , 77 ]. As a consequence, the eosinophil-derived Th2 cytokines IL4 and IL13 orchestrate scWAT browning and brown adipose tissue (BAT) thermogenesis [ 73 , 76 , 78 ] ( Figure 1 ).…”

“…Finally, AT transcriptome analysis identified AT-specific eosinophils reprogramming. Compared to blood eosinophils, ATE were endowed with tissue-specific TF activity such as KLF, CEBP, and Fos/Jun family members [ 19 , 30 ]. However, an updated understanding of ATE heterogeneity is still lacking and a thorough characterization is urgently needed.…”

“…Eosinophils can integrate cues from the tissue-shaping their tissue specific function. This is supported by evidence that tissue-resident eosinophils exhibit distinct properties from mature bone marrow (BM) or blood cells [ 19 , 30 ].…”