About 50 million Americans (22%) suffer from some form of arthritis and estimates are that, with the aging population worldwide, 67 million adults will have arthritis by 2030 with an economic impact higher than $128 billion dollars. Although interleukin-23 (IL-23) has been implicated in the pathogenesis of arthritis, the molecular mechanisms remain unknown. Since the discovery of IL-23 regulation of pathogenic T helper cells that express interleukin-17 (Th17) the importance of direct actions of IL-23 in arthritis is overshadowed. To highlight its importance we developed gene-transfer models of IL-23 and IL-17A and using these models we established that IL-23 is a potent inducer of arthritis, independently of IL-17A. Dissection of IL-23 from the IL- 23/IL-17A axis has allowed us to uncover novel mechanisms of myeloid cell activation previously overlooked. We identified that IL-23 induces arthritis independently of Th17 cells and through activation of myeloid cells. T cells and myeloid cells share a requirement for costimulatory signals that are mediated by ITAMs. The ITAM is a conserved signaling motif contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated and transmit signals from various immunoreceptors present in haematopoietic progenitors. These signals orchestrate synovial inflammation and differentiation of myeloid cells to bone resorbing cells called osteoclasts. Discovering the cellular and molecular mechanisms that dictate recruitment and activation of osteoclasts in inflammatory arthritis is central to preventing this disabling condition. Detailed understanding of these cellular and molecular interactions will yield insights into regulation of arthritis that can be exploited for therapeutic interventions.

Public Health Relevance

In this project we seek to study the molecular and cellular interactions that initiate arthritis. We have identified that IL-23 is a molecule that causes arthritis in animals. We also propose that the mechanism of arthritis initiation is independent of the traditional activation of specialized immune memory cells but it is dependent on the activation and specialized bone destroying cells called osteoclasts. Our research will provide the understanding towards the design of novel therapeutics for arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR062173-01
Application #
8222170
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$333,185
Indirect Cost
$108,185
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Nguyen, Cuong Thach; Bloch, Yehudi; Sk?adanowska, Katarzyna et al. (2018) Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight. Clin Immunol :
Bouchareychas, Laura; Grössinger, Eva M; Kang, Mincheol et al. (2018) ??TCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis. Sci Rep 8:7590
Bloch, Yehudi; Bouchareychas, Laura; Merceron, Romain et al. (2018) Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12R?1. Immunity 48:45-58.e6
Adamopoulos, Iannis E (2018) Inflammation in bone physiology and pathology. Curr Opin Rheumatol 30:59-64
Grössinger, Eva M; Kang, Mincheol; Bouchareychas, Laura et al. (2018) Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis. J Immunol 200:749-757
Marusina, Alina I; Ono, Yoko; Merleev, Alexander A et al. (2017) CD4+ virtual memory: Antigen-inexperienced T cells reside in the naïve, regulatory, and memory T cell compartments at similar frequencies, implications for autoimmunity. J Autoimmun 77:76-88
Wu, Dennis J; Adamopoulos, Iannis E (2017) Loss of WDFY3 ameliorates severity of serum transfer-induced arthritis independently of autophagy. Cell Immunol 316:61-69
Bouchareychas, Laura; Grössinger, Eva M; Kang, Mincheol et al. (2017) Critical Role of LTB4/BLT1 in IL-23-Induced Synovial Inflammation and Osteoclastogenesis via NF-?B. J Immunol 198:452-460
Fierro, Fernando A; Nolta, Jan A; Adamopoulos, Iannis E (2017) Concise Review: Stem Cells in Osteoimmunology. Stem Cells 35:1461-1467
Wang, Elizabeth A; Suzuki, Erika; Maverakis, Emanual et al. (2017) Targeting IL-17 in psoriatic arthritis. Eur J Rheumatol 4:272-277

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