About 50 million Americans (22%) suffer from some form of inflammatory 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 signalling motif contained in the cytoplasmic domain of transmembrane adaptor molecules that are associated and transmit signals from various immunoreceptors present in haematopoietic progenitors. We have identified that IL-23 induces the activation and recruitment of MDL-1 receptor that orchestrates synovial and skin inflammation via the activation of osteoclasts and neutrophils respectively. 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 investigate the role the IL-23/IL-17 axis in the activation of innate immunity and the modulation of cell differentiation programs leading to bone and skin pathology as commonly occurs in autoimmunity.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Mao, Su-Yau
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University of California Davis
Internal Medicine/Medicine
Schools of Medicine
United States
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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
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
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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