Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system.
FASEB J
; 26(12): 4977-89, 2012 Dec.
Article
in En
| MEDLINE
| ID: mdl-22964301
ABSTRACT
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 µg/mouse, â¼33 µmol) 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 µg/mouse, â¼12 nmol), and by minocycline (2.25 mg/mouse, â¼6.3 nmol). The nonselective Fpr agonists, fMLP (6 µg/mouse, â¼17 nmol) and AnxA1(Ac2-26), and the Fpr2-selective agonist ATLa (5 µg/mouse, â¼11 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain
/
Annexin A1
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Sepsis
/
Receptors, Formyl Peptide
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Inflammation
/
Leukocytes
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2012
Document type:
Article
Affiliation country:
United kingdom