Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1‐FPR2/ALX anti‐inflammatory system

Unregulated inflammation underlies many diseases, including sepsis. Much interest lies in targeting anti‐inflammatory mechanisms to develop new treatments. One such target is the anti‐inflammatory protein annexin A1 (AnxA1) and its receptor, FPR2/ALX. Using intravital videomicroscopy, we investigated the role of AnxA1 and FPR2/ALX in a murine model of endotoxin‐induced cerebral inflammation [intraperitoneal injection of lipopolysaccharide (LPS)]. An inflammatory response was confirmed by elevations in proinflammatory serum cytokines, increased cerebrovascular permeability, elevation in brain myeloperoxidase, and increased leukocyte rolling and adhesion in cerebral venules of wild‐type (WT) mice, which were further exacerbated in AnxA1‐null mice. mRNA expression of TLR2, TLR4, MyD‐88, and Ly96 was also assessed. The AnxA1‐mimetic peptide, AnxA1Ac2‐26 (100 μg/mouse, ~33 μmol) mitigated LPS‐induced leukocyte adhesion in WT and AnxA1‐null animals without affecting leukocyte rolling, in comparison to saline control. AnxA1Ac2‐26 effects were attenuated by Boc2 (pan‐FPR antagonist, 10 μg/mouse, ~12 nmol), and by minocycline (2.25 mg/mouse, ~6.3 nmol). The nonselective Fpr agonists, fMLP (6 μg/mouse, ~17 nmol) and AnxA1Ac2‐26, and the Fpr2‐selective agonist ATLa (5 μg/mouse, ~11 nmol) were without effect in Fpr2/3–/– mice. In summary, our novel results demonstrate that the AnxA1/FPR2 system has an important role in effecting the resolution of cerebral inflammation in sepsis and may, therefore, provide a novel therapeutic target.—Gavins, F. N. E., Hughes, E. L., Buss, N. A. P. S., Holloway, P. M., Getting, S. J., Buckingham, J. C. Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1‐FPR2/ALX anti‐inflammatory system. FASEB J. 26, 4977–4989 (2012). www.fasebj.org