4.8 Article

Sex differences in neutrophil biology modulate to I interferons and immunometabolism

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2003603117

Keywords

neutrophils; sex differences; interferons; innate immunity

Funding

  1. Intramural Research Programs at the National Institute of Arthritis and Musculoskeletal and Skin Diseases [ZIAAR04119]
  2. National Institute of Allergy and Infectious Diseases, NIH
  3. Swedish Research Council (Vetenskapsradet)
  4. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI001203] Funding Source: NIH RePORTER
  5. NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [ZIAAR041213, ZIHAR041173, ZIAAR041199, ZICAR041207] Funding Source: NIH RePORTER

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Differences between female and male immunity may contribute to variations in response to infections and predisposition to autoim-munity. 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 dif-ferential neutrophil phenotypes, we performed RNA sequencing on circulating neutrophils from healthy adult females and males. Fe-male 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. Neu-trophil hyperresponsiveness to type I IFNs promoted enhanced re-sponses to Toll-like receptor agonists. Neutrophils from young adult males had significantly increased mitochondrial metabolism com-pared 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 dis-tinct sex differences in neutrophil biology related to responses to type I IFNs, immunometabolism, and maturation status that may have prominent functional and pathogenic implications.

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