Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 332 (6028): 478-484

Copyright © 2011 by the American Association for the Advancement of Science

The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice

Wei Tang,1,2,* Yi Lu,1,2,* Qing-Yun Tian,1,* Yan Zhang,1 Feng-Jin Guo,1,{dagger} Guang-Yi Liu,1 Nabeel Muzaffar Syed,1 Yongjie Lai,1 Edward Alan Lin,1 Li Kong,1 Jeffrey Su,3 Fangfang Yin,4,{ddagger} Ai-Hao Ding,4 Alexandra Zanin-Zhorov,5 Michael L. Dustin,5 Jian Tao,6 Joseph Craft,6 Zhinan Yin,7 Jian Q. Feng,8 Steven B. Abramson,9 Xiu-Ping Yu,2 Chuan-ju Liu1,10,§

Abstract: The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.

1 Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.
2 Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
3 Cytovance Biologics, Oklahoma City, OK 73104, USA.
4 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
5 Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
6 Section of Rheumatology, Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
7 College of Life Sciences, Nankai University, Tianjin 300071, China.
8 Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, TX 75246, USA.
9 Division of Rheumatology, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.
10 Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.

* These authors contributed equally to this work.

{dagger} Present address: Chongqing Medical University, Chongqing, 400016, China.

{ddagger} Present address: SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.

§ To whom correspondence should be addressed. E-mail: chuanju.liu{at}med.nyu.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes.
B. M. Schwenk, C. M. Lang, S. Hogl, S. Tahirovic, D. Orozco, K. Rentzsch, S. F. Lichtenthaler, C. C. Hoogenraad, A. Capell, C. Haass, et al. (2014)
EMBO J. 33, 450-467
   Abstract »    Full Text »    PDF »
Progranulin, a Major Secreted Protein of Mouse Adipose-Derived Stem Cells, Inhibits Light-Induced Retinal Degeneration.
K. Tsuruma, M. Yamauchi, S. Sugitani, T. Otsuka, Y. Ohno, Y. Nagahara, Y. Ikegame, M. Shimazawa, S. Yoshimura, T. Iwama, et al. (2014)
Stem Cells Trans Med 3, 42-53
   Abstract »    Full Text »    PDF »
Progranulin is a substrate for neutrophil-elastase and proteinase-3 in the airway and its concentration correlates with mediators of airway inflammation in COPD.
M. J. Ungurs, N. J. Sinden, and R. A. Stockley (2014)
Am J Physiol Lung Cell Mol Physiol 306, L80-L87
   Abstract »    Full Text »    PDF »
ADAMTS-7 forms a positive feedback loop with TNF-{alpha} in the pathogenesis of osteoarthritis.
Y. Lai, X. Bai, Y. Zhao, Q. Tian, B. Liu, E. A. Lin, Y. Chen, B. Lee, C. T. Appleton, F. Beier, et al. (2013)
Ann Rheum Dis
   Abstract »    Full Text »
Progranulin Deficiency Promotes Post-Ischemic Blood-Brain Barrier Disruption.
K. Jackman, T. Kahles, D. Lane, L. Garcia-Bonilla, T. Abe, C. Capone, K. Hochrainer, H. Voss, P. Zhou, A. Ding, et al. (2013)
J. Neurosci. 33, 19579-19589
   Abstract »    Full Text »    PDF »
Activity-dependent secretion of progranulin from synapses.
E. Petoukhov, S. Fernando, F. Mills, F. Shivji, D. Hunter, C. Krieger, M. A. Silverman, and S. X. Bamji (2013)
J. Cell Sci. 126, 5412-5421
   Abstract »    Full Text »    PDF »
Utility of Progranulin and Serum Leukocyte Protease Inhibitor as Diagnostic and Prognostic Biomarkers in Ovarian Cancer.
A. M. Carlson, M. J. Maurer, K. M. Goergen, K. R. Kalli, C. L. Erskine, M. D. Behrens, K. L. Knutson, and M. S. Block (2013)
Cancer Epidemiol. Biomarkers Prev. 22, 1730-1735
   Abstract »    Full Text »    PDF »
Crosstalk of lipids and inflammation in atherosclerosis: the PRO of PGRN?.
S. C. A. de Jager and G. Pasterkamp (2013)
Cardiovasc Res 100, 4-6
   Full Text »    PDF »
Deletion of progranulin exacerbates atherosclerosis in ApoE knockout mice.
R. Kawase, T. Ohama, A. Matsuyama, T. Matsuwaki, T. Okada, T. Yamashita, M. Yuasa-Kawase, H. Nakaoka, K. Nakatani, M. Inagaki, et al. (2013)
Cardiovasc Res 100, 125-133
   Abstract »    Full Text »    PDF »
TDP-43 frontotemporal lobar degeneration and autoimmune disease.
Z. A. Miller, K. P. Rankin, N. R. Graff-Radford, L. T. Takada, V. E. Sturm, C. M. Cleveland, L. A. Criswell, P. A. Jaeger, T. Stan, K. A. Heggeli, et al. (2013)
J. Neurol. Neurosurg. Psychiatry 84, 956-962
   Abstract »    Full Text »    PDF »
Progranulin Does Not Bind Tumor Necrosis Factor (TNF) Receptors and Is Not a Direct Regulator of TNF-Dependent Signaling or Bioactivity in Immune or Neuronal Cells.
X. Chen, J. Chang, Q. Deng, J. Xu, T. A. Nguyen, L. H. Martens, B. Cenik, G. Taylor, K. F. Hudson, J. Chung, et al. (2013)
J. Neurosci. 33, 9202-9213
   Abstract »    Full Text »    PDF »
Secreted Progranulin Is a Homodimer and Is Not a Component of High Density Lipoproteins (HDL).
A. D. Nguyen, T. A. Nguyen, B. Cenik, G. Yu, J. Herz, T. C. Walther, W. S. Davidson, and R. V. Farese Jr. (2013)
J. Biol. Chem. 288, 8627-8635
   Abstract »    Full Text »    PDF »
Dissociation of Frontotemporal Dementia-Related Deficits and Neuroinflammation in Progranulin Haploinsufficient Mice.
A. J. Filiano, L. H. Martens, A. H. Young, B. A. Warmus, P. Zhou, G. Diaz-Ramirez, J. Jiao, Z. Zhang, E. J. Huang, F.-B. Gao, et al. (2013)
J. Neurosci. 33, 5352-5361
   Abstract »    Full Text »    PDF »
Insights into the role of progranulin in immunity, infection, and inflammation.
J. Jian, J. Konopka, and C. Liu (2013)
J. Leukoc. Biol. 93, 199-208
   Abstract »    Full Text »    PDF »
The novel growth factor, progranulin, stimulates mouse cholangiocyte proliferation via sirtuin-1-mediated inactivation of FOXO1.
G. Frampton, Y. Ueno, M. Quinn, M. McMillin, H. Y. Pae, C. Galindo, D. Leyva-Illades, and S. DeMorrow (2012)
Am J Physiol Gastrointest Liver Physiol 303, G1202-G1211
   Abstract »    Full Text »    PDF »
Circulating progranulin levels in women with gestational diabetes mellitus and healthy controls during and after pregnancy.
J. Todoric, A. Handisurya, T. Perkmann, B. Knapp, O. Wagner, A. Tura, G. Pacini, H. Esterbauer, and A. Kautzky-Willer (2012)
Eur. J. Endocrinol. 167, 561-567
   Abstract »    Full Text »    PDF »
Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration.
B. Cenik, C. F. Sephton, B. Kutluk Cenik, J. Herz, and G. Yu (2012)
J. Biol. Chem. 287, 32298-32306
   Abstract »    Full Text »    PDF »
The Tumor Necrosis Factor Receptor Stalk Regions Define Responsiveness to Soluble versus Membrane-Bound Ligand.
C. Richter, S. Messerschmidt, G. Holeiter, J. Tepperink, S. Osswald, A. Zappe, M. Branschadel, V. Boschert, D. A. Mann, P. Scheurich, et al. (2012)
Mol. Cell. Biol. 32, 2515-2529
   Abstract »    Full Text »    PDF »
Frontotemporal Dementia: Implications for Understanding Alzheimer Disease.
M. Goedert, B. Ghetti, and M. G. Spillantini (2012)
Cold Spring Harb Perspect Med 2, a006254
   Abstract »    Full Text »    PDF »
Tumor necrosis factor receptor 1 functions as a tumor suppressor.
F. Chang, M. R. Lacey, M. Bouljihad, K. H. z. Bentrup, and I. S. Fortgang (2012)
Am J Physiol Gastrointest Liver Physiol 302, G195-G206
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 26 April 2011.
C.-j. Liu and A. M. VanHook (2011)
Science Signaling 4, pc8
   Abstract »    Full Text »
Progranulin Resolves Inflammation.
H. Wu and R. M. Siegel (2011)
Science 332, 427-428
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882