Neutrophil Function Impacted by Sex Differences and Aging

According to USC researchers, the response of neutrophils to pathogens differs greatly by sex and by age. In a recent mouse study, the team found that males proved much more susceptible to sepsis than females. However, the scientists also found that the female disease-defense system is hardly perfect; their system changes with age to become nearly as harmful as the males'.

The study, published in Nature Aging today, has important implications for studying disease and cures, especially for sepsis, a condition in which the body's defense system turns harmful to itself. It also suggests that the quest for precision medicine may be overlooking more obvious disease determinants: age and sex.

"A big take-home message is that with the push for personalized medicine, people focus on minute genetic differences, but we find that biological sex—the biggest genetic difference of all —is actually a great predictor for immune response seldom taken into account," said Bérénice Benayoun, principal investigator of the study.

Benayoun and colleagues discovered differences in neutrophil activity between young and old mice, as well as between male and female mice. Males appeared to have more degranulation activity, as evidenced by higher levels of neutrophil elastase. Meanwhile females exhibited more NETosis (in which neutrophils expel strands of their own chromatin, which act as a trap outside of the cell) on average.

High degranulation activity can cause damage to surrounding tissues, and these findings could illustrate why sepsis affects men more than women, Benayoun said. "With sepsis, what kills you is not actually the bacteria; it's your response to the bacteria," she noted. "And we know that males in general have much worse odds during sepsis than females, and neutrophil elastase, which is one of the main components of degranulation, is one of the big things that can be produced at very high level during sepsis."

On the other hand, higher NETosis activity could contribute to the body's immune system attacking healthy cells, Benayoun added. Antibodies targeting the body's own DNA have been found in many autoimmune disorders, which could have been developed after neutrophils produced too many NETs. Thus, higher NET activity in females could be related to higher rates of autoimmune disorders in women.

With age, female neutrophils became more reactive, in contrast to male neutrophils. "In general, genetic programs seem to 'age' at a faster rate in male neutrophils," she said. "These findings suggest that sex differences can become amplified with aging, at least for neutrophils."