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. 2017 Mar;222(3):506-517.
doi: 10.1016/j.imbio.2016.10.018. Epub 2016 Oct 21.

Heme oxygenase 1 affects granulopoiesis in mice through control of myelocyte proliferation

Karolina Bukowska-Strakova  1 , Maciej Ciesla  2 , Krzysztof Szade  2 , Witold Norbert Nowak  2 , Robert Straka  3 , Agata Szade  2 , Malgorzata Tyszka-Czochara  4 , Karolina Najder  2 , Anna Konturek  2 , Maciej Siedlar  5 , Jozef Dulak  2 , Alicja Jozkowicz  6
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Heme oxygenase 1 affects granulopoiesis in mice through control of myelocyte proliferation

Karolina Bukowska-Strakova et al. Immunobiology. 2017 Mar.

Abstract

Heme oxygenase-1 (HO-1) is stress-inducible, cytoprotective enzyme degrading heme to carbon monoxide (CO), biliverdin and Fe2+. We showed that HO-1 knock-out mice (HO-1-/-) have a twofold higher level of granulocytes than wild type (WT) mice, despite decreased concentration of granulocyte colony-stimulating factor (G-CSF) in the blood and reduced surface expression of G-CSF receptor on the hematopoietic precursors. This suggests the effect of HO-1 on granulopoiesis. Here we aimed to determine the stage of granulopoiesis regulated by HO-1. The earliest stages of hematopoiesis were not biased toward myeloid differentiation in HO-1-/- mice. Within committed granulocytic compartment, in WT mice, HO-1 was up-regulated starting from myelocyte stage. This was concomitant with up-regulation of miR-155, which targets Bach1, the HO-1 repressor. In HO-1-/- mice granulopoiesis was accelerated between myelocyte and metamyelocyte stage. There was a higher fraction of proliferating myelocytes, with increased nuclear expression of pro-proliferative C/EBPβ (CCAAT/enhancer binding protein beta) protein, especially its active LAP (liver-enriched activator proteins) isoform. Also our mathematical model confirmed shortening the myelocyte cyclic-time and prolonged mitotic expansion in absence of HO-1. It seems that changes in C/EBPβ expression and activity in HO-1-/- myelocytes can be associated with reduced level of its direct repressor miR-155 or with decreased concentration of CO, known to reduce nuclear translocation of C/EBPs. Mature HO-1-/- granulocytes were functionally competent as determined by oxidative burst capacity. In conclusion, HO-1 influences granulopoiesis through regulation of myelocyte proliferation. It is accompanied by changes in expression of transcriptionally active C/EBPβ protein. As HO-1 expression vary in human and is up-regulated in response to chemotherapy, it can potentially influence chemotherapy-induced neutropenia.

Keywords: C/EBPβ; Carbon monoxide; Granulocyte colony-stimulating factor; Granulopoiesis; Heme oxygenase 1.

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