The inflammatory response is a complex condition that can be visualised
in terms of leukocyte activity at the microcirculatory level. Recent data
show that leukocyte recruitment can be prevented by both the endogenous
protein annexin A1 (AnxA1) and activation of its receptor FPR2/ALX
(murine orthologue: Fpr2), thus aiding resolution of the inflammation. Furthermore,
AnxA1 is sensitive to oestrogen (E2) and so is a candidate mediator
of the sex differences seen in many inflammatory diseases. Using intravital
microscopy to quantify leukocyte-endothelial cell interactions in the
murine mesentery in real-time and in vivo, we aimed to establish a model
of the systemic inflammatory response and determine the involvement of
the AnxA1-Fpr2 system in effecting anti-inflammation. Lipopolysaccharide
(LPS; 10 g/mouse I.P.) induced leukocyte rolling, adhesion and emigration,
and plasma protein extravasation, observable at 2, 6 and 24 h after injection
in mesenteric venules. At 2 h, leukocyte infiltration was also seen in
the liver and plasma concentrations of TNF- , IL-6 and IL-10 were raised,
indicating a systemic response. When given 20 min into, or at the end of, a
2 h LPS challenge, the Fpr2 ligands AnxA1Ac2-26 and LXA4 reduced LPS-induced
adhesion, an effect that was blocked by both antagonists that were
either pan-FPR (Boc2) or Fpr2-specific (WRW4). Our model also showed
sexual dimorphisms, in that LPS-induced leukocyte-endothelial cell interactions
and plasma TNF- and IL-10 concentrations were heightened in
females. Ovariectomy revealed a particular role for ovarian hormones besides
E2 in the manifestation of these differences, and the use of AnxA1-/-
mice suggests that AnxA1 reduces the animals’ sensitivity to E2. These
data suggest firstly that FPR2/ALX presents an attractive target for novel
anti-inflammatory therapeutics, and secondly that ovarian function is important
in the regulation of inflammation.