Complement Receptor 3 Contributes to the Sexual Dimorphism in Neutrophil Killing of Staphylococcus aureus

Abstract

We previously reported sex differences in innate susceptibility to Staphylococcus aureus skin infection and that bone marrow neutrophils (BMN) from female mice have an enhanced ability to kill S. aureus ex vivo compared with those of male mice. However, the mechanism(s) driving this sex bias in neutrophil killing have not been reported. Given the role of opsonins such as complement, as well as their receptors, in S. aureus recognition and clearance, we investigated their contribution to the enhanced bactericidal capacity of female BMN. We found that levels of C3 in the serum and CR3 (CD11b/CD18) on the surface of BMN were higher in female compared with male mice. Consistent with increased CR3 expression following TNF-α priming, production of reactive oxygen species (ROS), an important bactericidal effector, was also increased in female versus male BMN in response to serum-opsonized S. aureus. Furthermore, blocking CD11b reduced both ROS levels and S. aureus killing by murine BMN from both sexes. However, at the same concentration of CD11b blocking Ab, S. aureus killing by female BMN was greatly reduced compared with those from male mice, suggesting CR3-dependent differences in bacterial killing between sexes. Overall, this work highlights the contributions of CR3, C3, and ROS to innate sex bias in the neutrophil response to S. aureus. Given that neutrophils are crucial for S. aureus clearance, understanding the mechanism(s) driving the innate sex bias in neutrophil bactericidal capacity could identify novel host factors important for host defense against S. aureus.