Tumor necrosis factor-? TNF?) has received the greatest attention because of its position at the apex of the pro-inflammatory cytokine cascade, and its dominance in the pathogenesis of inflammation. Anti-TNF therapies have been accepted as the effective approach to treating inflammatory arthritis. In a global screen for the binding proteins of progranulin (PGRN) growth factor, we found that PGRN bound to TNFR1 and TNFR2. Subsequent studies demonstrated that PGRN protected regulatory T cells (Treg) from negative regulation by TNF?; Loss of PGRN signaling rendered B6 mice highly susceptible to collagen-induced arthritis (CIA), whereas recombinant PGRN prevented inflammation arthritis in CIA models;and in vivo treatment with PGRN stimulated IL-10 production in Treg cells and IL-10 signaling was important for PGRN-stimulated Treg function in vitro. These studies have led to the central hypothesis, that PGRN exerts its protective effects through its interaction with TNFR and stimulation of IL-10 producing Treg cells in the course of inflammatory arthritis.
The Specific Aims are: (1) To determine the roles of PGRN and underlying mechanisms in the pathogenesis of inflammatory arthritis. We will determine whether inducible knockout of PGRN worsens arthritic symptoms in mice with existing inflammatory arthritis. We hypothesize that the susceptible phenotype seen in PGRN deficient mice may be due to the low frequency of Treg cells. We will study the immune regulatory roles of PGRN in the pathogenesis of CIA, focusing on the role of PGRN and the underlying mechanisms in Treg development. (2) To elucidate TNFRs role in PGRN-mediated signaling in the pathogenesis of inflammatory arthritis. We will first compare the receptor complexes of TNF?/TNFR and PGRN/TNFR using tandem affinity purification, followed by mass spectrometry. We will also compare the key intracellular events of PGRN and TNF?, including signaling, target gene expression profiling, and activation of the NF?B pathway in human Treg cells isolated from normal and the patients with inflammatory arthritis. Furthermore, we will elucidate which TNFR is important for mediating PGRNs protective role in CIA by using TNFR1-/- and TNFR2-/- mice. (3) To define the role of IL-10 in mediating PGRN action in the pathogenesis of inflammatory arthritis. To gain insight into the mechanisms of already known therapies of PGRN, we will use IL-10-GFP reporter tiger mice and Foxp3 RFP reporter FIR mice to identify the IL-10 expressing non-Treg cells and Treg cells in response to gain- or loss-of- PGRN in CIA, which would provide more insight on why PGRN-deficient B6 mice become highly susceptible to CIA, and whether IL-10 is the target of PGRN in CIA. To test the hypothesis that PGRN via IL-10 mediates the observed therapeutic effect upon CIA, we will determine if adoptive transfer of PGRN-induced IL-10-expressing Tregs can suppress CIA, and whether blockage of IL-10 signaling inhibits PGRNs effects on CIA. The proposed studies will not only provide new insights into the pathogenesis of CIA, but also lead to the development of novel therapeutic strategies for inflammatory arthritis and other TNFR-mediated pathologies and conditions.
Herein this application we propose to determine the immunological mechanism underlying PGRN-mediated protective function in inflammatory arthritis. In addition, PGRN and its potential target IL-10 anti-inflammatory cytokine may also offer new therapeutic interventions for other TNF/TNFR-mediated inflammatory diseases such as systemic lupus erythematosus, inflammatory bowel disease (Crohn's diseases, Ulcerative Colitis), ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis.
|Zhao, Yun-peng; Wei, Jian-lu; Tian, Qing-yun et al. (2016) Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNFÎ± signaling. Sci Rep 6:20909|
|Mundra, Jyoti Joshi; Jian, Jinlong; Bhagat, Priyal et al. (2016) Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner. Sci Rep 6:21115|
|Wei, Jian-Lu; Buza 3rd, John; Liu, Chuan-Ju (2016) Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?: Comment on Olson et al.: ""Therapeutic Opportunities to Prevent Post-Traumatic Arthritis: Lessons From the Natural History of Arthritis After Art J Orthop Res 34:12-4|
|Jian, Jinlong; Tian, Qing-Yun; Hettinghouse, Aubryanna et al. (2016) Progranulin Recruits HSP70 to Î²-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease. EBioMedicine :|
|Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun et al. (2016) Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. FASEB J 30:2741-54|
|Jian, Jinlong; Li, Guangfei; Hettinghouse, Aubryanna et al. (2016) Progranulin: A key player in autoimmune diseases. Cytokine :|
|Uddin, S M Z; Richbourgh, B; Ding, Y et al. (2016) Chondro-protective effects of low intensity pulsed ultrasound. Osteoarthritis Cartilage 24:1989-1998|
|Zhang, Yuying; Wei, Fanhua; Liu, Chuan-Ju (2015) Overexpression of ADAMTS-7 leads to accelerated initiation and progression of collagen-induced arthritis in mice. Mol Cell Biochem 404:171-9|
|Zhao, Hua; Gonzalezgugel, Elena; Cheng, Lei et al. (2015) The roles of interferon-inducible p200 family members IFI16 and p204 in innate immune responses, cell differentiation and proliferation. Genes Dis 2:46-56|
|Zhao, Yun-Peng; Liu, Ben; Tian, Qing-Yun et al. (2015) Progranulin protects against osteoarthritis through interacting with TNF-Î± and Î²-Catenin signalling. Ann Rheum Dis 74:2244-53|
Showing the most recent 10 out of 28 publications