Progesterone promotes Cxcl2-dependent vaginal neutrophil killing by activating cervical resident macrophage-neutrophil crosstalk

Vaginal infections in women of reproductive age represent a clinical dilemma with significant socio-economic implications. The understanding of mucosal immunity failure during early pathogenic invasions that allow the pathogen to grow and thrive is far from complete. Neutrophils infiltrate most tissues following circadian patterns as part of normal repair, regulation of microbiota, or immune surveillance and become more numerous after infection. Neutrophils are responsible for maintaining vaginal immunity. Specific to the vagina, neutrophils continuously infiltrate at high levels, although during ovulation they retreat to avoid sperm damage and permit reproduction. Here we show that after ovulation, progesterone promotes resident vaginal macrophage-neutrophils crosstalk by up-regulating Yolk sac and early fetal organs (Folr2+ (folate receptor 2)) macrophage Cxcl2 expression, in a Tnfa-monocyte-derived macrophage (Cx3cr1hi MHCIIhi) mediated manner, to activate neutrophils' capacity to eliminate sex-transmitted and opportunistic microorganisms. Indeed, progesterone plays an essential role in conciliating the balance between the commensal microbiota, sperm, and the threat of pathogens: because progesterone not only promotes a flurry of neutrophils but also increases neutrophilic fury to restore immunity after ovulation to thwart pathogenic invasion post-intercourse. Therefore, modest progesterone dysregulations could lead to a suboptimal neutrophilic response, resulting in insufficient mucosal defense and recurrent unresolved infections.