TNF?/TNFR has received the greatest attention because of its position at the apex of the pro-inflammatory cy- tokine cascade, and its dominance in the pathogenesis of inflammation. TNFR1 primarily mediates inflammato- ry activity of TNF?, whereas TNFR2 plays a protective and anti-inflammatory role in various diseases. Our ge- netic screen for the binding partners of progranulin (PGRN) growth factor led to the isolation of TNFR2 as the PGRN-binding receptor (Tang, et al, Science, 2011). Remarkably, PGRN exhibits an approximately 600-fold higher binding affinity to TNFR2 than does TNF?. During the initial funding period, we have successfully identi- fied in a proteomics screen 14-3-3?, an important intracellular signaling molecule, as a novel component of TNFR2 complexes in response to PGRN stimulation. PGRN deficiency promoted inflammatory classically- activated macrophage (CAM) but inhibited anti-inflammatory alternatively-activated macrophage (AAM) polari- zation, whereas recombinant PGRN inhibited AAM-CAM but stimulated CAM-AAM switching. In addition, knockout of 14-3-3? abolished PGRN?s regulation of macrophage. More excitingly, our direct protein-protein interaction screen of nine central members of the complement system identified C5a as a novel binding partner of PGRN with high binding affinity, and PGRN inhibited the binding of C5a to C5aR1. Thus, the scientific prem- ise of this competitive continued application is based on 1) the identification of 14-3-3? as a novel component of PGRN/TNFR2 pathway, and 2) the isolation of C5a as a novel PGRN-binding factor. The central hypothesis is that PGRN regulates macrophage polarization and inflammatory arthritis through a) recruitment of 14-3-3? to TNFR2 and activation of the PGRN/TNFR2 anti-inflammatory pathway; and b) interplay with C5a and inhibition of C5a/C5aR1 inflammatory pathway.
The Specific Aims are: (1) To elucidate 14-3-3??s role in PGRN/TNFR2- mediated macrophage polarization in the course of inflammatory arthritis. We will determine the dependence on 14-3-3? of PGRN's regulation of macrophage polarization (SA#1.1); the signaling, target genes and co- factor(s) of 14-3-3? that mediate PGRN action in macrophage polarization (SA#1.2); and the importance of PGRN regulation of macrophage phenotypic switch in the context of inflammatory arthritis and its dependence on 14-3-3? (SA#1.3). (2) To define the importance of PGRN/C5a interplay in the pathogenesis of inflammatory arthritis. We will characterize and dissect the PGRN/C5a interaction and to identify PGRN-derived minimal fragment/peptide that retains C5a binding activity (SA#2.1); elucidate the interplay between PGRN and C5a in regulating macrophage polarization, as well as the signaling pathways involved (SA#2.2); and determine the interplay between PGRN and C5a/C5aR1 signaling and the contribution of inhibition of C5a/C5aR1 signaling by PGRN to PGRN's anti-inflammatory action in inflammatory arthritis (SA#2.3). The proposed research will not only advance our understanding of the pathogenesis of inflammatory arthritis, but may also lead to the de- velopment of new interventions for various TNFR- and C5a/C5aR1-related conditions and diseases.

Public Health Relevance

In this application we propose to determine the immunological mechanism underlying PGRN-mediated protec- tive function in inflammatory arthritis. In addition, PGRN and its potential target TNFR2/14-3-3? anti- inflammatory and C5a/C5aR1 proinflammatory pathways may also offer new therapeutic interventions for other TNFR- and C5a-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)
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Innate Immunity and Inflammation Study Section (III)
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Mao, Su-Yau
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New York University
Schools of Medicine
New York
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