# The immunological mechanism of PGRNs anti-inflammatory effect - Renewal - 1

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $536,957

## Abstract

Project Description
TNFα/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 TNFα, 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 TNFα. During the initial funding period, we have successfully identi-
fied in a proteomics screen 14-3-3ε, 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 14-3-3ε 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 14-3-3ε 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 14-3-3ε 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 14-3-3ε’s role in PGRN/TNFR2-
mediated macrophage polarization in the course of inflammatory arthritis. We will determine the dependence
on 14-3-3ε of PGRN's regulation of macrophage polarization (SA#1.1); the signaling, target genes and co-
factor(s) of 14-3-3ε 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 14-3-3ε (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). Th...

## Key facts

- **NIH application ID:** 9836804
- **Project number:** 5R01AR062207-07
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Chuanju Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,957
- **Award type:** 5
- **Project period:** 2012-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836804

## Citation

> US National Institutes of Health, RePORTER application 9836804, The immunological mechanism of PGRNs anti-inflammatory effect - Renewal - 1 (5R01AR062207-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9836804. Licensed CC0.

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