title: Annexin A1 Is a Physiological Modulator of Neutrophil Maturation and Recirculation Acting on the CXCR4/CXCL12 Pathway.
abstract: Neutrophil production and traffic in the body compartments is finely controlled, and the strong evidences support the role of CXCL12/CXCR4 pathway on neutrophil trafficking to and from the bone marrow (BM). We recently showed that the glucocorticoid-regulated protein, Annexin A1 (AnxA1) modulates neutrophil homeostasis and here we address the effects of AnxA1 on steady-state neutrophil maturation and trafficking. For this purpose, AnxA1(-/-) and Balb/C wild-type mice (WT) were donors of BM granulocytes and mesenchymal stem cells and blood neutrophils. In vivo treatments with the pharmacological AnxA1 mimetic peptide (Ac2-26) or the formyl peptide receptor (FPR) antagonist (Boc-2) were used to elucidate the pathway of AnxA1 action, and with the cytosolic glucocorticoid antagonist receptor RU 38486. Accelerated maturation of BM granulocytes was detected in AnxA1(-/-) and Boc2-treated WT mice, and was reversed by treatment with Ac2-26 in AnxA1(-/-) mice. AnxA1 and FPR2 were constitutively expressed in bone marrow granulocytes, and their expressions were reduced by treatment with RU38486. Higher numbers of CXCR4(+) neutrophils were detected in the circulation of AnxA1(-/-) or Boc2-treated WT mice, and values were rescued in Ac2-26-treated AnxA1(-/-) mice. Although circulating neutrophils of AnxA1(-/-) animals were CXCR4(+) , they presented reduced CXCL12-induced chemotaxis. Moreover, levels of CXCL12 were reduced in the bone marrow perfusate and in the mesenchymal stem cell supernatant from AnxA1(-/-) mice, and in vivo and in vitro CXCL12 expression was re-established after Ac2-26 treatment. Collectively, these data highlight AnxA1 as a novel determinant of neutrophil maturation and the mechanisms behind blood neutrophil homing to BM via the CXCL12/CXCR4 pathway. J. Cell. Physiol. 231: 2418-2427, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Isabel Daufenback
authors.initials: ID
authors.lastname: Machado
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Marina
authors.initials: M
authors.lastname: Spatti
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Araceli
authors.initials: A
authors.lastname: Hastreiter
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: José Roberto
authors.initials: JR
authors.lastname: Santin
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Ricardo Ambrósio
authors.initials: RA
authors.lastname: Fock
authors.affiliation: Department of Morphology and Genetics, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil.
authors.forename: Cristiane Damas
authors.initials: CD
authors.lastname: Gil
authors.affiliation: Department of Biology, Instituto de Biociências, Letras e Ciências Exatas (IBILCE), São Paulo State University (UNESP), São José do Rio Preto, São Paulo, Brazil.
authors.forename: Sonia Maria
authors.initials: SM
authors.lastname: Oliani
authors.affiliation: Centre for Biochemical Pharmacology, The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.affiliation: Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil.
authors.forename: Sandra Helena Poliselli
authors.initials: SH
authors.lastname: Farsky
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D002339:Carotid Arteries / Q000166:cytology; D002452:Cell Count; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D002633:Chemotaxis; D008168:Lung / Q000098:blood supply; D008297:Male; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000097:blood; D015398:Signal Transduction
chemical_list: D017305:Annexin A1; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D044042:Receptors, Formyl Peptide; D023063:Receptors, Interleukin-8B