Extracellular annexin-A1 promotes myeloid/granulocytic differentiation of hematopoietic stem/progenitor cells via the Ca2+/MAPK signalling transduction pathway

Abstract

Annexin A1 (AnxA1) modulates neutrophil life span and bone marrow/blood cell trafficking thorough activation of formyl-peptide receptors (FPRs). Here, we investigated the effect of exogenous AnxA1 on haematopoiesis in the mouse. Treatment of C57BL/6 mice with recombinant AnxA1 (rAnxA1) reduced the granulocyte–macrophage progenitor (GMP) population in the bone marrow, enhanced the number of mature granulocytes Gr-1+Mac-1+ in the bone marrow as well as peripheral granulocytic neutrophils and increased expression of mitotic cyclin B1 on hematopoietic stem cells (HSCs)/progenitor cells (Lin−Sca-1+c-Kit+: LSK). These effects were abolished by simultaneous treatment with Boc-2, an FPR pan-antagonist. In in vitro studies, rAnxA1 reduced both HSC (LSKCD90lowFLK-2−) and GMP populations while enhancing mature cells (Gr1+Mac1+). Moreover, rAnxA1 induced LSK cell proliferation (Ki67+), increasing the percentage of cells in the S/G2/M cell cycle phases and reducing Notch-1 expression. Simultaneous treatment with WRW4, a selective FPR2 antagonist, reversed the in vitro effects elicited by rAnxA1. Treatment of LSK cells with rAnxA1 led to phosphorylation of PCLγ2, PKC, RAS, MEK, and ERK1/2 with increased expression of NFAT2. In long-term bone marrow cultures, rAnxA1 did not alter the percentage of LSK cells but enhanced the Gr-1+Mac-1+ population; treatment with a PLC (U73122), but not with a PKC (GF109203), inhibitor reduced rAnxA1-induced phosphorylation of ERK1/2 and Elk1. Therefore, we identify here rAnxA1 as an inducer of HSC/progenitor cell differentiation, favouring differentiation of the myeloid/granulocytic lineage, via Ca2+/MAPK signalling transduction pathways.

Annexin Animal Models—From Fundamental Principles to Translational Research

“…Interestingly, AnxA1 not only impacts on neutrophil homeostasis in the presence of glucocorticoids, but also seems to modulate steady-state neutrophil maturation [ 31 ]. In efforts to clarify the role of exogenous AnxA1 for the hematopoietic system, administration of AnxA1, most likely via FPR-induced Ca 2+ and MAPK signalling, promotes myeloid and granulocytic differentiation [ 41 ].…”

Role of Annexin A1 in Squamous Cell Lung Cancer Progression

“…The earliest discovered role of ANXA1 was its anti-inflammatory role to suppress neutrophils and modulated monocytes recruitment [9]. Dysregulation of ANXA1 expression has been reported to contribute to the pathophysiology of multiple processes, such as tumorigenesis and autoinflammatory diseases [10][11][12][13][14][15][16].…”

Therapeutic effects of Sheng Xue Fang in a cyclophosphamide-induced anaemia mouse model

“… 2018 ; Barbosa et al. 2019 ). IL-6 plays a role in blocking erythropoiesis during the pro-erythropoiesis phase and blocking anti-human IL-6 antibodies can improve acute myeloid leukemia-induced anaemia and extend overall survival (Zhang et al.…”