Neutrophils are key modulators of sex differences in LPS-induced shock in mice.

Lipopolysaccharide (LPS) exposure in mice induces robust morbidity and mortality, and is widely used as a model for sepsis. However, the role of biological sex in modulating immune responses during LPS-induced sepsis remains incompletely understood. In this study, we investigated how sex influences immune responses following LPS challenge in mice. Using age-matched mice, we found that during primary LPS challenge, females exhibited significantly higher mortality than males. This difference correlated with greater production of proinflammatory cytokines in females. Further analysis revealed that female myeloid cells expressed higher levels of Toll-like receptor 4, and displayed enhanced activation of NF-κB and MAPK signaling. Additionally, compared with males, female macrophages expressed significantly more inducible nitric oxide synthase but less arginase, supporting a sex-based divergence in inflammatory response to LPS. Interestingly, during lethal LPS rechallenge, the sex bias was reversed, with higher mortality observed in males than in females. These findings suggest that males had a survival advantage during the primary LPS challenge, while females exhibited greater resistance during rechallenge, emphasizing the need for careful consideration of sex-based differences in sepsis models. Neutrophils played a critical role in these sex-based differences. Neutrophil depletion significantly increased susceptibility to both primary and secondary LPS challenge. Notably, the sex bias in LPS-induced shock disappeared in neutrophil-depleted mice, highlighting a previously unrecognized role for neutrophils in mitigating LPS-induced mortality and maintaining sex-based differences in sepsis outcome.