Increased ILC3s associated with higher levels of IL-1β aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase

Tzu-Yi Chan; Chia-Liang Yen; Ya-Fang Huang; Pei-Chi Lo; Peter A Nigrovic; Chia-Ying Cheng; Wei-Zhi Wang; Szu-Yu Wu; Chi-Chang Shieh

doi:10.1002/eji.201948141

Increased ILC3s associated with higher levels of IL-1β aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase

Eur J Immunol. 2019 Nov;49(11):2063-2073. doi: 10.1002/eji.201948141. Epub 2019 Aug 6.

Authors

Tzu-Yi Chan¹, Chia-Liang Yen¹, Ya-Fang Huang², Pei-Chi Lo³, Peter A Nigrovic^{4

5}, Chia-Ying Cheng¹, Wei-Zhi Wang¹, Szu-Yu Wu¹, Chi-Chang Shieh^{1

6}

Affiliations

¹ Institute of Clinical Medicine, National Cheng-Kung University Medical College, Tainan, Taiwan.
² National Laboratory Animal Center, National Applied Research Laboratories, Tainan, Taiwan.
³ Division of Organ Transplantation, Department of Surgery, Osaka University. Graduate School of Medicine, Osaka, Japan.
⁴ Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
⁶ Department of Pediatrics, National Cheng-Kung University Hospital, Tainan, Taiwan.

PMID: 31350760
DOI: 10.1002/eji.201948141

Abstract

The role of redox regulation in immune-mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte-derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL-1 family cytokines along with other cytokines relevant to ILC functions and development in serum-induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)-deficient Ncf1^-/- mice. We found more severe serum-induced joint inflammation and increased NCR⁺ ILC3s in inflamed joints of Ncf1^-/- mice. Furthermore, in vitro stimulation with IL-1β on Tbet⁺ ILC1s from joints facilitated their differentiation into ROR-γt⁺ ILC3s. Moreover, treatment with IL-1 antagonists effectively lowered the proportions of NCR⁺ ILC3s and IL-17A producing ILC3s in Ncf1^-/- arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential regulator of ILC transdifferentiation and may mediate this process in a redox-dependent manner through IL-1β production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell-mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints.

Keywords: NADPH oxidase; chronic granulomatous disease; innate lymphoid cells; reactive oxygen species; serum-induced arthritis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antirheumatic Agents / pharmacology
Arthritis, Experimental / chemically induced
Arthritis, Experimental / drug therapy
Arthritis, Experimental / immunology
Arthritis, Experimental / pathology
Gene Expression Regulation / immunology
Immunity, Innate / drug effects
Interleukin 1 Receptor Antagonist Protein / pharmacology
Interleukin-17 / genetics
Interleukin-17 / immunology
Interleukin-1beta / genetics
Interleukin-1beta / immunology*
Lymphocytes / drug effects
Lymphocytes / immunology*
Lymphocytes / pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidase 2 / deficiency*
NADPH Oxidase 2 / genetics
NADPH Oxidase 2 / immunology
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
Oxidation-Reduction / drug effects
Phagocytes / drug effects
Phagocytes / immunology
Phagocytes / pathology
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / immunology*
Serum / immunology
Signal Transduction
T-Box Domain Proteins / genetics
T-Box Domain Proteins / immunology
Tarsus, Animal / drug effects
Tarsus, Animal / immunology*
Tarsus, Animal / pathology

Substances

Antirheumatic Agents
IL1B protein, mouse
Il17a protein, mouse
Interleukin 1 Receptor Antagonist Protein
Interleukin-17
Interleukin-1beta
Nuclear Receptor Subfamily 1, Group F, Member 3
Reactive Oxygen Species
Rorc protein, mouse
T-Box Domain Proteins
T-box transcription factor TBX21
Cybb protein, mouse
NADPH Oxidase 2