Evidence for an anti-inflammatory loop centered on polymorphonuclear leukocyte formyl peptide receptor 2/lipoxin A4 receptor and operative in the inflamed microvasculature

J Immunol. 2011 Apr 15;186(8):4905-14. doi: 10.4049/jimmunol.1003145. Epub 2011 Mar 11.

Abstract

The importance of proresolving mediators in the overall context of the resolution of acute inflammation is well recognized, although little is known about whether these anti-inflammatory and proresolving molecules act in concert. In this article, we focused on lipoxin A(4) (LXA(4)) and annexin A1 (AnxA1) because these two very different mediators converge on a single receptor, formyl peptide receptor type 2 (FPR2/ALX). Addition of LXA(4) to human polymorphonuclear leukocytes (PMNs) provoked a concentration- and time-dependent mobilization of AnxA1 onto the plasma membrane, as determined by Western blotting and flow cytometry analyses. This property was shared by another FPR2/ALX agonist, antiflammin-2, and partly by fMLF or peptide Ac2-26 (an AnxA1 derivative that can activate all three members of the human FPR family). An FPR2/ALX antagonist blocked AnxA1 mobilization activated by LXA(4) and antiflammin-2. Analysis of PMN degranulation patterns and phospho-AnxA1 status suggested a model in which the two FPR2/ALX agonists mobilize the cytosolic (and not the granular) pool of AnxA1 through an intermediate phosphorylation step. Intravital microscopy investigations of the inflamed mesenteric microvasculature of wild-type and AnxA1(-/-) mice revealed that LXA(4) provoked leukocyte detachment from the postcapillary venule endothelium in the former (>50% within 10 min; p < 0.05), but not the latter genotype (∼15%; NS). Furthermore, recruitment of Gr1(+) cells into dorsal air-pouches, inflamed with IL-1β, was significantly attenuated by LXA(4) in wild-type, but not AnxA1(-/-), mice. Collectively, these data prompt us to propose the existence of an endogenous network in anti-inflammation centered on PMN AnxA1 and activated by selective FPR2/ALX agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A1 / genetics
  • Annexin A1 / immunology
  • Annexin A1 / metabolism
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Blotting, Western
  • Cell Membrane / metabolism
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • Humans
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / prevention & control
  • Inflammation Mediators / immunology
  • Inflammation Mediators / metabolism
  • Lipoxins / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microvessels / immunology*
  • Microvessels / metabolism
  • Microvessels / pathology
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Oligopeptides / pharmacology
  • Peptide Fragments / pharmacology
  • Protein Transport / drug effects
  • Receptors, Formyl Peptide / immunology*
  • Receptors, Formyl Peptide / metabolism
  • Receptors, Lipoxin / immunology*
  • Receptors, Lipoxin / metabolism
  • Time Factors

Substances

  • Annexin A1
  • Anti-Inflammatory Agents, Non-Steroidal
  • FPR2 protein, human
  • Inflammation Mediators
  • Lipoxins
  • Oligopeptides
  • Peptide Fragments
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • lipoxin A4
  • antiflammin P2