Annexin A1 Is a Physiological Modulator of Neutrophil Maturation and Recirculation Acting on the CXCR4/CXCL12 Pathway

Author(s)

Machado, Isabel Daufenback ; Spatti, Marina ; Hastreiter, Araceli ; Santin, Jose Roberto ; Fock, Ricardo Ambrosio ; Gil, Cristiane Damas ; Oliani, Sonia Maria ; Perretti, Mauro ; Poliselli Farsky, Sandra Helena

• Document type: Journal article
• Source: Journal of Cellular Physiology; v. 231, n. 11, p. 2418-2427, NOV 2016.
• Web of Science Citations: 8

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. (C) 2016 Wiley Periodicals, Inc. (AU)

• FAPESP's process: 10/16828-0 - Molecular mechanisms of endogenous glucocorticoids on neutrophil traffic: actions on SDF-1alfa/CXCR-4 and IL-17/IL-23/G-CSF axis
• Grantee: Sandra Helena Poliselli Farsky
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/07328-4 - Identification of endogenous pathways for the control of inflammation
• Grantee: Sandra Helena Poliselli Farsky
• Support Opportunities: Research Projects - Thematic Grants