Role and interactions of annexin A1 and oestrogens in the manifestation of sexual dimorphisms in cerebral and systemic inflammation

Background and Purpose Gender differences in inflammation are well described, with females often showing more robust, oestrogen‐associated responses. Here, we investigated the influence of gender, oestrogen and the anti‐inflammatory protein annexin A1 (AnxA1) on lipopolysaccharide (LPS)‐induced leukocyte–endothelial cell interactions in murine cerebral and mesenteric microvascular beds. Experimental Approach Intravital microscopy was used to visualize and quantify the effects of LPS (10 μg·per mouse i.p.) on leukocyte–endothelial interactions in male and female wild‐type (WT) mice. The effects of ovariectomy ± oestrogen replacement were examined in WT and AnxA1‐null (AnxA1−/−) female mice. Key Results LPS increased leukocyte adherence in the cerebral and mesenteric beds of both male and female WT mice; females showed exacerbated responses in the brain versus males, but not the mesentery. Ovariectomy further enhanced LPS‐induced adhesion in the brain but not the mesentery; its effects were reversed by oestrogen treatment. OVX AnxA1−/− mice also showed exaggerated adhesive responses to LPS in the brain. However, these were unresponsive to ovariectomy and, paradoxically, responded to oestrogen with a pronounced increase in basal and LPS‐induced leukocyte adhesion in the cerebrovasculature. Conclusions and Implications Our data confirm the fundamental role of AnxA1 in limiting the inflammatory response in the central and peripheral microvasculature. They also (i) show that oestrogen acts via an AnxA1‐dependent mechanism to protect the cerebral, but not the mesenteric, vasculature from the damaging effects of LPS and (ii) reveal a paradoxical and potentially toxic effect of the steroid in potentiating the central response to LPS in the absence of AnxA1.