The role of annexin A1 in the manifestation of sexual dimorphisms in cerebral and systemic inflammatory responses to endotoxin

The inflammatory response is sexually dimorphic, with females of child‐bearing age being less prone to morbidity and mortality than males. Since the anti‐inflammatory protein annexin A1 (AnxA1) is partly upregulated by oestrogen we investigated the role of oestrogen in modulating neuro and systemic protection of AnxA1 experimental sepsis. Endotoxaemia was induced in male and female wild‐type (WT) mice (i.p. lipopolysaccharide (LPS)). Leukocyte endothelial cell (L/EC) interactions were quantified using intravital microscopy. The effects of ovarietomy +/− oestrogen replacement therapy in WT and AnxA1‐null female mice were examined, to dissect the involvement of oestrogen in mediating the effects of AnxA1. LPS increased L/EC interactions in both vascular beds. Ovariectomy increased LPS‐induced leukocyte adhesion in WT mice in the cerebral and mesenteric vascular beds, and these effects were reversed by oestrogen replacement. However, in the brains of ovariectomised AnxA1‐null female mice, oestrogen replacement potentiated LPS‐induced leukocyte adhesion and TNF‐α production. Our data suggests oestrogen facilitates cellular interactions during sepsis, aiding more efficient pathogen clearance. However, AnxA1 within the brain limits a potentially damaging cerebrovascular inflammatory response, which is otherwise enhanced by oestrogen.