The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice
By Wei Tang, Yi Lu, Q. Tian, Yan Zhang, F. Guo, Guang-Yi Liu, Nabeel Muzaffar Syed, Y. Lai, E. Lin, L. Kong and 12 more. Science, 2011
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A growth factor protects against arthritis in mice by blocking tumor necrosis factor–dependent signaling. 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.
Subfields: Genetics, Molecular Biology, Neurology
View Paper: https://www.semanticscholar.org/paper/56a63b90888b34d5d95fdf5901c9f2b60bd97cfd
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- The Role of Inflammatory and Anti-Inflammatory Cytokines in the Pathogenesis of Osteoarthritis (2014, background): “It is worth to mention the presence of an additional ligand capable of incorporating both TNF-R1 and TNF-R2 with still increasing importance in the pathogenesis of OA, which is progranulin (PGRN) also known as granulin epithelin precursor (GEP), PC-cell derived growth factor (PCDGF), proepithelin (P”
- Regulation of tumour necrosis factor signalling: live or let die (2015, background): “However, the benefits of these treatments outweigh the rare occurrences of these side effects. of three PGRN fragments, prevented TNF-mediated inflammation 167 .”
- B–helper neutrophils stimulate immunoglobulin diversification and production in the marginal zone of the spleen (2011, background): “, and immunoregulatory molecules such as IL-10, the IL-10 receptor, arginase 1, RALDH1, iNOS, IDO, SOCS1, progranulin and SLP”