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.
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.
|Suzuki, Erika; Maverakis, Emanual; Sarin, Ritu et al. (2016) T Cell-Independent Mechanisms Associated with Neutrophil Extracellular Trap Formation and Selective Autophagy in IL-17A-Mediated Epidermal Hyperplasia. J Immunol 197:4403-4412|
|Wu, Dennis J; Gu, Ran; Sarin, Ritu et al. (2016) Autophagy-linked FYVE containing protein WDFY3 interacts with TRAF6 and modulates RANKL-induced osteoclastogenesis. J Autoimmun 73:73-84|
|JimÃ©nez-Dalmaroni, Maximiliano Javier; Gerswhin, M Eric; Adamopoulos, Iannis E (2016) The critical role of toll-like receptors--From microbial recognition to autoimmunity: A comprehensive review. Autoimmun Rev 15:1-8|
|Adamopoulos, Iannis E; Suzuki, Erika; Chao, Cheng-Chi et al. (2015) IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis. Ann Rheum Dis 74:1284-92|
|Adamopoulos, Iannis E (2015) Autoimmune or Autoiflammatory? Bad to the Bone. Int J Clin Rheumtol 10:5-7|
|Adamopoulos, Iannis E; Mellins, Elizabeth D (2015) Alternative pathways of osteoclastogenesis in inflammatory arthritis. Nat Rev Rheumatol 11:189-94|
|Shin, Hyun-Seock; Sarin, Ritu; Dixit, Neha et al. (2015) Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis. J Immunol 194:316-24|
|Wu, Dennis J; Dixit, Neha; Suzuki, Erika et al. (2014) A novel in vivo gene transfer technique and in vitro cell based assays for the study of bone loss in musculoskeletal disorders. J Vis Exp :|
|Orosco, Lori A; Ross, Adam P; Cates, Staci L et al. (2014) Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology. Nat Commun 5:4692|
|Suzuki, Erika; Mellins, Elizabeth D; Gershwin, M Eric et al. (2014) The IL-23/IL-17 axis in psoriatic arthritis. Autoimmun Rev 13:496-502|
Showing the most recent 10 out of 14 publications