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Hematopoiesis
Alas1 is essential for neutrophil maturation in zebrafish
Ferrata Storti Foundation
Junwei Lian,1 Jiakui Chen,1 Kun Wang,1 Lingfeng Zhao,1 Ping Meng,1
Liting Yang,1 Jiayi Wei,1 Ning Ma,1 Jin Xu,2 Wenqing Zhang2 and Yiyue Zhang1,2
1Key Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases of Guangdong Higher Education Institutes, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University and 2Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, P.R. China
Haematologica 2018 Volume 103(11):1785-1795
ABSTRACT
Neutrophils play essential roles in innate immunity and are the first responders to kill foreign micro-organisms, a function that partial- ly depends on their granule content. The complicated regulatory network of neutrophil development and maturation remains largely unknown. Here we utilized neutrophil-deficient zebrafish to identify a novel role of Alas1, a heme biosynthesis pathway enzyme, in neutrophil development. We showed that Alas1-deficient zebrafish exhibited prop- er neutrophil initiation, but further neutrophil maturation was blocked due to heme deficiency, with lipid storage and granule formation defi- ciencies, and loss of heme-dependent granule protein activities. Consequently, Alas1-deficient zebrafish showed impaired bactericidal ability and augmented inflammatory responses when challenged with Escherichia coli. These findings demonstrate the important role of Alas1 in regulating neutrophil maturation and physiological function through the heme. Our study provides an in vivo model of Alas1 deficiency and may be useful to evaluate the progression of heme-related disorders in order to facilitate the development of drugs and treatment strategies for these diseases.
Introduction
Neutrophils are the most abundant leukocytes in the circulation and the first responders to sites of infection, where they attack pathogens by phagocytosis, degranulation, and by generating neutrophil extracellular traps.1,2 Neutrophil devel- opment is highly conserved in vertebrates, making zebrafish a suitable model for investigation. Neutrophils are derived from granulocyte-monocyte progenitors, and undergo determination and differentiation from myeloblasts to mature neu- trophils.1,3 During neutrophil differentiation and maturation, neutrophil granules are formed and assembled.1 Anti-microbial proteins are thought to be the major constituents of neutrophil granules, and they play important roles in neutrophil diapedesis, chemotaxis, and the phagocytosis of micro-organisms.1,4
Several transcription factors have been reported to be involved in neutrophil development and physiological function in mammals, including SPI.1/PU1 and C/EBP-ε.3 A recent study of embryonic myelopoiesis revealed that the Pu.1-Runx1 regulatory loop controlled embryonic myeloid cell fate in zebrafish.5,6 We previous- ly demonstrated that c-Myb and Cebp1 co-operatively acted in parallel to govern neutrophil maturation.7 In addition to these transcription factors, zebrafish defi- cient for the neutrophil granule protein myeloperoxidase (Mpx) or the neutrophil- specific marker nephrosin (Npsn) have altered neutrophil maturation and inflam- matory responses to fungal and bacterial infection, respectively.8,9 Nevertheless, the complicated regulatory network of neutrophil maturation, as well as the impact on physiological function remain poorly understood.
Heme (iron protoporphyrin IX) functions as a prosthetic group on various pro- teins, so-called hemoproteins, such as hemoglobin, myoglobin, cytochromes, cata- lases, and peroxidases.10 Hemoproteins are involved in diverse biological functions, including oxygen transport, energy metabolism, and drug biotransformation.11 Moreover, heme also plays important roles in the regulation of transcription,12-14
Correspondence:
yiyue@smu.edu.cn or mczhangyy@scut.edu.cn or mczhangwq@scut.edu.cn
Received: March 27, 2018. Accepted: June 27, 2018. Pre-published: June 28, 2018
doi:10.3324/haematol.2018.194316
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1785
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