Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells

Kihyun Lee, Hee Yeon Won, Myung Ae Bae, Jeong-Ho Hong, Eun Sook Hwang

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Emerging evidence indicates that NADPH oxidase (NOX) and its reactive oxygen species (ROS) products modulate a variety of cellular events, including proliferation, differentiation, and apoptosis. In this study, we investigated the functions of NOX2 and ROS in immune modulation using NOX2 knockout (KO) mice. Interestingly, NOX2 KO mice spontaneously developed arthritis with onset at 6-7 wk of age and high incidence (60%) at 15-18 wk of age. Arthritis severity in NOX2 KO mice was proportionally increased with age and higher in females than in males. Bone destruction was confirmed by microcomputed tomography scanning and histological analyses of joints. Inflammatory factors, including TNF-α, IL-1β, and RANKL, and serum level of anti-type II collagen IgG were significantly increased in NOX2 KO mice. In addition, NOX2 deficiency perturbed the immune system upon aging. NOX2 KO mice demonstrated preferred development of CD11b+Gr-1+ myeloid cells with profound production of proinflammatory cytokines and augmented expression of IL-17 through the activation of STAT3 and RORγt in vivo. NOX2 deficiency increased differentiation of effector Th cells in vitro and decreased CD25+FoxP3+ Treg cells both in vitro and in vivo. Furthermore, adoptive transfer of NOX2-deficient CD4+ T cells into RAG KO mice increased arthritic inflammation compared with WT cells. These results demonstrated that NOX2 deficiency affected the development of CD11b+ myeloid cells and Th17/Treg cells, and thus promoted inflammatory cytokine production and inflammatory arthritis development, strongly supporting a crucial role for ROS generation in the modulation of Th17/Treg cell development and its related inflammatory immune response upon aging.

Original languageEnglish
Pages (from-to)9548-9553
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number23
DOIs
Publication statusPublished - 2011 Jun 7

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NADPH Oxidase
Regulatory T-Lymphocytes
Knockout Mice
Arthritis
Th17 Cells
Reactive Oxygen Species
Myeloid Cells
Cytokines
X-Ray Microtomography
Collagen Type II
Interleukin-17
Adoptive Transfer
Interleukin-1
Immune System
Immunoglobulin G
Joints
Apoptosis
Inflammation
T-Lymphocytes
Bone and Bones

Keywords

  • Myeloid-derived suppressor cell
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • General

Cite this

Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+ and Th/Treg cells. / Lee, Kihyun; Won, Hee Yeon; Bae, Myung Ae; Hong, Jeong-Ho; Hwang, Eun Sook.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 23, 07.06.2011, p. 9548-9553.

Research output: Contribution to journalArticle

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