Journal article
TNFR2/14-3-3 signaling complex instructs macrophage plasticity in inflammation and autoimmunity
The Journal of clinical investigation, Vol.131(16)
16 Aug 2021
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3c as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3c was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3c resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3c signaled through PI3K/ Akt/mTOR to restrict NF-KB activation while simultaneously stimulating C/EBPp activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3c as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3c antiinflammatory pathway.
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Details
- Title
- TNFR2/14-3-3 signaling complex instructs macrophage plasticity in inflammation and autoimmunity
- Creators
- Wenyu Fu - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Wenhuo Hu - Memorial Sloan Kettering Cancer CenterYoung-Su Yi - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Aubryanna Hettinghouse - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Guodong Sun - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Yufei Bi - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Wenjun He - NYU, Grossman Sch Med, Dept Orthoped Surg, 301 East 17th St, New York, NY 10003 USALei Zhang - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Guanmin Gao - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Jody Liu - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.Kazuhito Toyo-oka - Drexel UniversityGuozhi Xiao - Southern University of Science and TechnologyDavid B. Solit - Memorial Sloan Kettering Cancer CenterPng Loke - NYU, Dept Microbiol, Grossman Sch Med, New York, NY 10016 USAChuan-ju Liu - Department of Orthopaedic Surgery, New York University Medical Center, New York, United States of America.
- Publication Details
- The Journal of clinical investigation, Vol.131(16)
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 18
- Grant note
- W81XWH1610482 / Department of Defense research grant; United States Department of Defense R01AR062207; R01AR061484; R01AR076900; R01NS103931; R01NS096098 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Identifiers
- 991019167346404721
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- Domestic collaboration
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- Web of Science research areas
- Medicine, Research & Experimental