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, Guang-Yi Liu,¹ Nabeel Muzaffar Syed,¹ Yongjie Lai,¹ Edward Alan Lin,¹ Li Kong,¹ Jeffrey Su,³ Fangfang Yin,^4, 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 Liu^1,10,

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.

Present address: Chongqing Medical University, Chongqing, 400016, China.

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

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