Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism
Sarthak Gupta, View ORCID ProfileShuichiro Nakabo, View ORCID ProfileLuz P. Blanco, Liam J. O’Neil, Gustaf Wigerblad, View ORCID ProfileRishi R. Goel, Pragnesh Mistry, Kan Jiang, View ORCID ProfileCarmelo Carmona-Rivera, Diana W. Chan, Xinghao Wang, View ORCID ProfileHege L. Pedersen, Manasi Gadkari, View ORCID ProfileKatherine N. Howe, Faiza Naz, Stefania Dell’Orso, View ORCID ProfileSarfaraz A. Hasni, Caeden Dempsey, Ashley Buscetta, Pamela A. Frischmeyer-Guerrerio, View ORCID ProfilePaul Kruszka, Maximilian Muenke, View ORCID ProfileLuis M. Franco, Hong-Wei Sun, and View ORCID ProfileMariana J. Kaplan
PNAS first published June 29, 2020 https://doi.org/10.1073/pnas.2003603117
Abstract
Differences between female and male immunity may contribute to variations in response to infections and predisposition to autoimmunity. We previously reported that neutrophils from reproductive-age males are more immature and less activated than their female counterparts. To further characterize the mechanisms that drive differential neutrophil phenotypes, we performed RNA sequencing on circulating neutrophils from healthy adult females and males. Female neutrophils displayed significant up-regulation of type I IFN (IFN)-stimulated genes (ISGs). Single-cell RNA-sequencing analysis indicated that these differences are neutrophil specific, driven by a distinct neutrophil subset and related to maturation status. Neutrophil hyperresponsiveness to type I IFNs promoted enhanced responses to Toll-like receptor agonists. Neutrophils from young adult males had significantly increased mitochondrial metabolism compared to those from females and this was modulated by estradiol. Assessment of ISGs and neutrophil maturation genes in Klinefelter syndrome (47, XXY) males and in prepubescent children supported that differences in neutrophil phenotype between adult male and female neutrophils are hormonally driven and not explained by X chromosome gene dosage. Our results indicate that there are distinct sex differences in neutrophil biology related to responses to type I IFNs, immunometabolism, and maturation status that may have prominent functional and pathogenic implications.
