| First Author | Gavins FN | Year | 2012 |
| Journal | FASEB J | Volume | 26 |
| Issue | 12 | Pages | 4977-89 |
| PubMed ID | 22964301 | Mgi Jnum | J:193581 |
| Mgi Id | MGI:5468786 | Doi | 10.1096/fj.12-205971 |
| Citation | Gavins FN, et al. (2012) Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system. FASEB J 26(12):4977-89 |
| abstractText | 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, AnxA1(Ac2-26) (100 mug/mouse, approximately 33 mumol) mitigated LPS-induced leukocyte adhesion in WT and AnxA1-null animals without affecting leukocyte rolling, in comparison to saline control. AnxA1(Ac2-26) effects were attenuated by Boc2 (pan-FPR antagonist, 10 mug/mouse, approximately 12 nmol), and by minocycline (2.25 mg/mouse, approximately 6.3 nmol). The nonselective Fpr agonists, fMLP (6 mug/mouse, approximately 17 nmol) and AnxA1(Ac2-26), and the Fpr2-selective agonist ATLa (5 mug/mouse, approximately 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. |
