# Fn14, non-canonical NF-kappaB and downstream signaling in neuropathic pain

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $373,122

## Abstract

BACKGROUND: The ongoing opioid epidemic is driven in part by legitimate use of opioids prescribed for
neuropathic pain. Targeting alternative pathways for pain control using non-addicting drugs is a major goal of
neuropathic pain research. After peripheral nerve injury (PNI), cytokines and chemokines are upregulated
centrally, where they contribute mechanistically to the pathogenesis of neuropathic pain. Reactive astrocytes in
the dorsal horn exhibit a chronically activated, pro-inflammatory secretory (CAPS) phenotype characterized by
secretion of numerous factors, including interleukin-6 (IL-6), chemokine C-C motif ligand 2 (CCL2), chemokine
C-X-C motif ligand 1 (CXCL1) and nerve growth factor (NGF). The post-PNI astrocytic CAPS phenotype
contributes to both inflammation and neuronal hyperactivation via neuronal chemokine receptors, leading to
neuropathic pain. Canonical NF-κB signaling is known to play a crucial role, but surprisingly, despite its
documented importance in numerous inflammatory conditions involving most organs including the brain, non-
canonical NF-κB signaling via the p52:RelB heterodimer has not been identified previously in PNI. New work
from our laboratory demonstrates the novel finding that non-canonical NF-κB signaling by the tumor necrosis
factor-like weak inducer of apoptosis (TWEAK) / fibroblast growth factor-inducible 14 (Fn14) axis is prominent
after PNI, especially in dorsal horn astrocytes, and may be responsible for transcriptional expression of Sur1-
Trpm4 in these cells. Moreover, our preliminary data suggest that glial Sur1-Trpm4 plays a crucial role in
regulating the expression of IL-6, CCL2 and CXCL1. Our central hypothesis is that, in dorsal horn astrocytes
post-PNI, TWEAK-induced non-canonical NF-κB signaling is an upstream regulator of Sur1-Trpm4 expression,
and that Sur1-Trpm4, in turn, regulates the expression of the downstream effectors, IL-6, CCL2 and CXCL1,
which promote chronic neuroinflammation, neuronal hyperactivation and neuropathic pain.
DESCRIPTION: This project has three mechanistic aims. In Aim 1, genetic (Tweak–/–, Fn14–/–, p100–/–,
Abcc8–/–, either global or GFAP-specific or GFAP-&-site-specific) and pharmacological (anti-TWEAK antibody,
glibenclamide) experiments will be carried out to determine the role of non-canonical NF-κB and Sur1 in
GFAP-expressing glia in sciatic n. vs. dorsal horn in two neuropathic pain models: sciatic n. cuffing and sciatic
n. exposure to HIV/gp120 protein. In Aim 2, we will expand upon in vivo and in vitro data from chromatin
immunoprecipitation to establish the role of non-canonical NF-κB in the expression of functional Sur1-Trpm4
channels. In Aim 3, we will corroborate and expand upon in vivo and in vitro data to establish the role of Sur1-
Trpm4 in regulating Ca2+/calcineurin-dependent transcription of IL-6, CCL2 and CXCL1. This project is the first
to study non-canonical NF-κB in dorsal horn vs. sciatic n. glia in neuropathic pain, and will help identify nove...

## Key facts

- **NIH application ID:** 9936459
- **Project number:** 5R01NS105633-03
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** J. Marc Simard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,122
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936459

## Citation

> US National Institutes of Health, RePORTER application 9936459, Fn14, non-canonical NF-kappaB and downstream signaling in neuropathic pain (5R01NS105633-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9936459. Licensed CC0.

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