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

Br J Pharmacol. 2013 Jun;169(3):539-53. doi: 10.1111/j.1476-5381.2012.02146.x.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1 / genetics
  • Annexin A1 / metabolism*
  • Cell Adhesion
  • Cell Communication
  • Cerebral Cortex / blood supply
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / immunology
  • Cerebral Cortex / metabolism*
  • Encephalitis / drug therapy
  • Encephalitis / immunology
  • Encephalitis / metabolism*
  • Encephalitis / pathology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Estradiol / metabolism
  • Estradiol / therapeutic use
  • Estrogen Replacement Therapy
  • Estrogens / metabolism*
  • Estrogens / therapeutic use
  • Female
  • Leukocytes / drug effects
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Leukocytes / pathology
  • Lipopolysaccharides
  • Male
  • Mesentery / blood supply
  • Mesentery / immunology
  • Mesentery / metabolism
  • Mesentery / pathology
  • Mice
  • Mice, Knockout
  • Microvessels / drug effects
  • Microvessels / immunology
  • Microvessels / metabolism*
  • Microvessels / pathology
  • Neurons / drug effects
  • Neurons / immunology
  • Neurons / metabolism*
  • Ovariectomy / adverse effects
  • Sex Characteristics
  • Systemic Vasculitis / drug therapy
  • Systemic Vasculitis / immunology
  • Systemic Vasculitis / metabolism*
  • Systemic Vasculitis / pathology


  • Annexin A1
  • Estrogens
  • Lipopolysaccharides
  • annexin A1, mouse
  • lipopolysaccharide, Escherichia coli O111 B4
  • Estradiol