title: Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system.
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, ∼33 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, ∼12 nmol), and by minocycline (2.25 mg/mouse, ∼6.3 nmol). The nonselective Fpr agonists, fMLP (6 μg/mouse, ∼17 nmol) and AnxA1(Ac2-26), 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.
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Burlington Danes Bldg., Du Cane Rd., London W12 0NN, UK. f.gavins@imperial.ac.uk
authors.forename: Felicity N E
authors.initials: FN
authors.lastname: Gavins
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Hughes
authors.forename: Nicholas A P S
authors.initials: NA
authors.lastname: Buss
authors.forename: Paul M
authors.initials: PM
authors.lastname: Holloway
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Getting
authors.forename: Julia C
authors.initials: JC
authors.lastname: Buckingham
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002560:Cerebrovascular Circulation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D036904:Leukocyte Rolling / Q000187:drug effects / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D051218:Lymphocyte Antigen 96 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018715:Microscopy, Video; D008911:Minocycline / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics
chemical_list: D017305:Annexin A1; D016207:Cytokines; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D009842:Oligopeptides; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D051193:Toll-Like Receptors; C573274:annexin A1, mouse; C481578:formyl peptide receptor 2, mouse; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine; D008911:Minocycline