Interferon regulatory factor-8-driven myeloid differentiation is regulated by 12/15-lipoxygenase-mediated redox signaling.
OBJECTIVE
Several transcription factors determine the cell fate decision between granulocytes and monocytes, but the upstream signal transduction pathways that govern myelopoiesis are largely unknown. Based on our observation of aberrant myeloid cell representation in hematopoietic tissues of 12/15-lipoxygenase (12/15-LOX)-deficient (Alox15) mice, we tested the hypothesis that polyunsaturated fatty acid metabolism regulates myelopoiesis.


METHODS
Multicolor flow cytometric analysis and methylcellulose assays were used to compare myelopoiesis and the differentiative capacity of progenitors from Alox15 and wild-type mice. Furthermore, we elucidated the mechanism by which 12/15-LOX is involved in regulation of myelopoiesis.


RESULTS
Granulopoiesis in Alox15 mice is increased while monopoiesis is reduced. Moreover, there is an accumulation of granulocyte-macrophage progenitors that exhibit defective differentiation. Mechanistically, we demonstrate that transcriptional activity of interferon regulatory factor-8 (Irf8), which regulates myelopoiesis, is impaired in Alox15 progenitors and bone marrow-derived macrophages due to loss of 12/15-LOX-mediated redox regulation of Irf8 nuclear accumulation. Restoration of redox signaling in Alox15 bone marrow cells and granulocyte-macrophage progenitors reversed the defect in myeloid differentiation.


CONCLUSIONS
These data establish 12/15-LOX-mediated redox signaling as a novel regulator of myelopoiesis and Irf8.
Kinder
Michelle
M
The Wistar Institute, Philadelphia, PA 19104, USA.
Thompson
James E
JE
Wei
Cong
C
Shelat
Suresh G
SG
Blair
Ian A
IA
Carroll
Martin
M
Puré
Ellen
E
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000378:metabolism; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism; D015151:Immunoblotting; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007377:Interleukin-3 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000378:metabolism*; D038042:Myelopoiesis / Q000187:drug effects; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000099185:Interferon Regulatory Factor-8
D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D004921:Erythropoietin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D050835:Interferon Regulatory Factors; D007377:Interleukin-3; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D000099185:Interferon Regulatory Factor-8; C475064:12-15-lipoxygenase