Annexin A1 Is a Physiological Modulator of Neutrophil Maturation and Recirculation Acting on the CXCR4/CXCL12 Pathway
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2016-11-01
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Machado, Isabel Daufenback
Spatti, Marina
Hastreiter, Araceli
Santin, José Roberto
Fock, Ricardo Ambrósio
Gil, Cristiane Damas
Oliani, Sonia Maria [UNESP]
Perretti, Mauro
Farsky, Sandra Helena Poliselli
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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.
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Journal of Cellular Physiology, v. 231, n. 11, p. 2418-2427, 2016.