Tumor necrosis factor-a (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 re-combinant 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 TNFR's 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 PGRN's 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 PGRN's effects on CIA. The pro- posed 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Schools of Medicine
New York
United States
Zip Code
Lata, Michal; Hettinghouse, Aubryanna S; Liu, Chuan-Ju (2018) Targeting tumor necrosis factor receptors in ankylosing spondylitis. Ann N Y Acad Sci :
Jian, Jinlong; Chen, Yuehong; Liberti, Rossella et al. (2018) Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease. EBioMedicine 28:251-260
Wei, Jian-Lu; Liu, Chuan-Ju (2018) Establishment of a Modified Collagen-Induced Arthritis Mouse Model to Investigate the Anti-inflammatory Activity of Progranulin in Inflammatory Arthritis. Methods Mol Biol 1806:305-313
Hettinghouse, Aubryanna; Liu, Ronghan; Liu, Chuan-Ju (2018) Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. Pharmacol Ther 181:34-48
Chen, Yuehong; Jian, Jinlong; Hettinghouse, Aubryanna et al. (2018) Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease. J Mol Med (Berl) 96:1359-1373
Yi, Young-Su; Jian, Jinlong; Gonzalez-Gugel, Elena et al. (2018) p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice. EBioMedicine 29:78-91
Wei, Jian-Lu; Fu, Wenyu; Hettinghouse, Aubryanna et al. (2018) Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor. Arthritis Rheumatol 70:1745-1756
Chen, Yuehong; Sud, Neetu; Hettinghouse, Aubryanna et al. (2018) Molecular regulations and therapeutic targets of Gaucher disease. Cytokine Growth Factor Rev 41:65-74
Jian, Jinlong; Li, Guangfei; Hettinghouse, Aubryanna et al. (2018) Progranulin: A key player in autoimmune diseases. Cytokine 101:48-55
Wei, Jian-Lu; Fu, Wenyu; Ding, Yuan-Jing et al. (2017) Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models. Arthritis Res Ther 19:280

Showing the most recent 10 out of 41 publications