There are striking differences between men and women in their ability to respond to certain infections, predisposition to and prognosis in certain cancers, and risk for developing an autoimmune disease. However, the underlying mechanisms that drive the differences between the male and female immune system remain insufficiently characterized, especially for innate immune system cells like neutrophils. This work showed that female neutrophils have striking upregulation of type I interferon (IFN) stimulated genes (ISGs), suggesting an enhanced response to this group of antiviral cytokines. In addition, the sex differences in type I IFN response observed were specific to neutrophils and not seen in other immune cell types. Therefore, the sex differences were likely related to the enhanced maturation and activation status of female cells when compared to male neutrophils.

What is exciting about this article?

In addition to the upregulated ISGs in female neutrophils, the researchers also identified differences in the cellular metabolism of female and male neutrophils. This difference appeared to be driven by sex hormones, such as estradiol. In addition, the differences in neutrophil phenotype and function between adult males and females were not observed in prepubertal boys and girls, further supporting a role of sex hormones, rather than the X chromosome. Also, neutrophils from subjects with Klinefelter’s syndrome (XXY karyotype) did not differ in their type I IFN response when compared to young males without Klinefelter’s. This study also identified several novel subsets of neutrophils in the peripheral blood of healthy young adults, suggesting that neutrophils are significantly more heterogeneous than previously appreciated.

How does this fit into the larger NIAMS portfolio?

This study demonstrates important sex differences in neutrophil function that may contribute to sex differences observed in autoimmunity, cancers, and infections. The effect of hormones on neutrophil responses presents an opportunity to develop them as potential therapeutics in infectious and autoimmune diseases. The identification of distinct subtypes of neutrophils, even in healthy subjects, could present targets for aberrant neutrophil responses in inflammatory conditions, bringing new opportunities for precision medicine.

Research Areas:



Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism.

Gupta S, Nakabo S, Blanco LP, O'Neil LJ, Wigerblad G, Goel RR, Mistry P, Jiang K, Carmona-Rivera C, Chan DW, Wang X, Pedersen HL, Gadkari M, Howe KN, Naz F, Dell'Orso S, Hasni SA, Dempsey C, Buscetta A, Frischmeyer-Guerrerio PA, Kruszka P, Muenke M, Franco LM, Sun HW, Kaplan MJ
Proc Natl Acad Sci U S A.
2020 Jul 14;
doi: 10.1073/pnas.2003603117
PMID: 32601182

Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.