Mice Deficient in NOX2 Display Severe Thymic Atrophy, Lymphopenia, and Reduced Lymphopoiesis in a Zymosan-Induced Model
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ORIGINAL ARTICLE
Mice Deficient in NOX2 Display Severe Thymic Atrophy, Lymphopenia, and Reduced Lymphopoiesis in a Zymosan-Induced Model of Systemic Inflammation Yu Sugimoto,1 Daiki Endo,1 and Yasuaki Aratani
1,2
(Received July 2, 2020; accepted September 8, 2020)
Patients with chronic granulomatous disease (CGD) who have mutated phagocyte NADPH oxidase are susceptible to infections due to reduced reactive oxygen species production and exhibit autoimmune and inflammatory diseases in the absence of evident infection. Neutrophils and macrophages have been extensively studied since phagocyte NADPH oxidase is mainly found only in them, while the impact of its deficiency on lymphocyte cellularity is less well characterized. We showed herein a zymosan-induced systemic inflammation model that CGD mice deficient in the phagocyte NADPH oxidase gp91phox subunit (NOX2) exhibited more severe thymic atrophy associated with peripheral blood and splenic lymphopenia and reduced lymphopoiesis in the bone marrow in comparison with the wildtype mice. Conversely, the zymosan-exposed CGD mice suffered from more remarkable neutrophilic lung inflammation, circulating and splenic neutrophilia, and enhanced granulopoiesis compared with those in zymosan-exposed wild-type mice. Overall, this study provided evidence that NOX2 deficiency exhibits severe thymic atrophy and lymphopenia concomitant with enhanced neutrophilic inflammation in a zymosan-induced systemic inflammation model.
Abstract—
KEY WORDS: phagocyte NADPH oxidase; lymphocytes; neutrophils; zymosan.
INTRODUCTION Neutrophils and macrophages play a vital role in host defense against pathogens like bacteria and
1
Graduate School of Nanobioscience, Yokohama City University, Seto 22-2, Kanazawa, Yokohama, 236-0027, Japan 2 To whom correspondence should be addressed at Graduate School of Nanobioscience, Yokohama City University, Seto 22-2, Kanazawa, Yokohama, 236-0027, Japan. E-mail: [email protected]
fungi. The most efficient microbicidal system employed by the phagocytes depends on reactive oxygen species (ROS) [1]. Activated neutrophils and macrophages generate superoxide anions (O 2-) via phagocyte NADPH oxidase, a multi-subunit enzyme consisting of two membranous subunits, gp91phox (also known as NOX2) and p22phox, and four cytoplasmic subunits, p67phox, p47phox, p40phox, and Rac2 [2, 3]. Chronic granulomatous disease (CGD) is a rare genetic disease caused by mutations in any one of the
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Sugimoto, Endo, and Aratani NADPH oxidase subunits [4, 5]. Patients with CGD are prone to recurrent infections, and they suffer from increased inflammatory responses in many organs including the lungs, skin, and gastrointestinal tract [6–8]. Similar to patients with CGD, NOX2 knockout mice (CGD mice) exhibit increased susceptibility to infection by various pathogens like Aspergillus fumigatus [9, 10] and Candida albicans [11, 12]. Fungal infections are the major causes of pneumonia an
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