Ayako Tanimura1,2, Keiko Miyoshi2, Taigo Horiguchi2, Hiroko Hagita2, Koichi Fujisawa3,4, Takafumi Noma2. 1. Department of Food and Health Sciences, Faculty of Environmental and Symbiotic Sciences, Prefectural University of Kumamoto, Kumamoto, Japan. 2. Department of Molecular Biology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. 3. Center of Research and Education for Regenerative Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan. 4. Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Abstract
BACKGROUND/AIMS: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in hematopoietic differentiation. However, the mechanistic linkage between ER stress/UPR and hematopoietic differentiation remains unclear. METHODS: We used bipotent HL-60 cells as an in vitro hematopoietic differentiation system to investigate the role of ER stress and UPR activity in neutrophil and macrophage differentiation. RESULTS: The in vitro differentiation analysis revealed that ER stress decreased during both neutrophil and macrophage differentiations, and the activities of PERK and ATF6 were decreased and that of IRE1α was increased during neutrophil differentiation in a stage-specific manner. By contrast, the activities of ATF6 and ATF4 decreased during macrophage differentiation. When the cells were treated with oligomycin, the expression of CD11b, a myelocytic differentiation marker, and morphological differentiation were suppressed, and XBP-1 activation was inhibited during neutrophil differentiation, whereas CD11b expression was maintained, and morphological differentiation was not obviously affected during macrophage differentiation. CONCLUSION: In this study, we demonstrated that neutrophil differentiation is regulated by ER stress/UPR that is supported by mitochondrial ATP supply, in which IRE1α-XBP1 activation is essential. Our findings provide the evidence that mitochondrial energy metabolism may play a critical role in neutrophil differentiation.
BACKGROUND/AIMS: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in hematopoietic differentiation. However, the mechanistic linkage between ER stress/UPR and hematopoietic differentiation remains unclear. METHODS: We used bipotent HL-60 cells as an in vitro hematopoietic differentiation system to investigate the role of ER stress and UPR activity in neutrophil and macrophage differentiation. RESULTS: The in vitro differentiation analysis revealed that ER stress decreased during both neutrophil and macrophage differentiations, and the activities of PERK and ATF6 were decreased and that of IRE1α was increased during neutrophil differentiation in a stage-specific manner. By contrast, the activities of ATF6 and ATF4 decreased during macrophage differentiation. When the cells were treated with oligomycin, the expression of CD11b, a myelocytic differentiation marker, and morphological differentiation were suppressed, and XBP-1 activation was inhibited during neutrophil differentiation, whereas CD11b expression was maintained, and morphological differentiation was not obviously affected during macrophage differentiation. CONCLUSION: In this study, we demonstrated that neutrophil differentiation is regulated by ER stress/UPR that is supported by mitochondrial ATP supply, in which IRE1α-XBP1 activation is essential. Our findings provide the evidence that mitochondrial energy metabolism may play a critical role in neutrophil differentiation.
Authors: Vidyanath Chaudhary; Marie Dominique Ah Kioon; Sung-Min Hwang; Bikash Mishra; Kimberly Lakin; Kyriakos A Kirou; Jeffrey Zhang-Sun; R Luke Wiseman; Robert F Spiera; Mary K Crow; Jessica K Gordon; Juan R Cubillos-Ruiz; Franck J Barrat Journal: J Exp Med Date: 2022-09-02 Impact factor: 17.579