# Inflammatory signaling in depression regulated by Toll-like receptors 2 and 4

> **NIH VA I01** · MIAMI VA HEALTH CARE SYSTEM · 2020 · —

## Abstract

The objective of this project is to determine how inflammatory signaling by Toll-like receptor-2 (TLR2)
and TLR4 regulate depression-like behaviors in mice to develop new therapeutic targets for major
depression. This exciting possibility is based on our novel Preliminary Results showing that TLR4
signaling increases susceptibility to depression onset modeled in mice, whereas TLR2 signaling
promotes recovery from depression. These balancing mood-regulating actions of inflammatory receptors
typifies the immune system characteristic of balancing signals in order to respond to damage or infection,
but limiting the response to avoid damage to the host. This is an important subject because major
depression is highly prevalent and debilitating in veterans, and therapies are often not adequate. Novel
targets need to be identified to develop new therapies, and the inflammatory system is one such novel
target, as substantial evidence demonstrates inflammatory activation promotes depression. We also
propose that drug development may have been limited by a primary focus on modulating onset in animal
models, whereas recovery from depression is equally important for therapy development. By giving equal
weight to examining susceptibility and recovery and examining receptors that mediate inflammatory
signaling, our Preliminary Results demonstrate that TLR4 promotes onset and TLR2 provides the
balance by promoting recovery from depression. Our overall hypothesis is that TLR-mediated signals
regulate maintenance of mood homeostasis, whereas abnormalities in TLR actions promote the
development and prolongation of depression. Testing this hypothesis will establish the potential for drugs
acting on TLR2 and TLR4 to bolster resistance to depression and support recovery. Specific Aim 1 will
test the hypothesis that TLR2 and TLR4 oppositely regulate depression-like behavior in mice. A panel of
behavioral assessments widely used to model depression-like behaviors will be applied to TLR2 and
TLR4 knockout mice, with and without antidepressant treatment, examining both onset and recovery.
Specific Aim 2 will test behavioral outcomes of pharmacologically modulating TLR2 and TLR4. We will
test the hypothesis that TLR2 agonists and TLR4 antagonists are antidepressant. Specific Aim 3 will test
mechanisms that regulate recovery from depressive-like behavior. We will test mechanisms that regulate
signaling involved in recovery from depression, such as cytokines and brain-derived neurotrophic factor
(BDNF), and examine proteins reported to be involved in mood regulation, to identify those critical for the
pro-depressant effect of TLR4 stimulation and depression-recovery facilitating effect of TLR2 stimulation.
Altogether this is an innovative project examining TLR2/4 as feasible therapeutic targets to reduce the
susceptibility and duration of depression modeled in mice, an important problem affecting the health of
many veterans.

## Key facts

- **NIH application ID:** 9859331
- **Project number:** 5I01BX003678-03
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** RICHARD S. JOPE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859331

## Citation

> US National Institutes of Health, RePORTER application 9859331, Inflammatory signaling in depression regulated by Toll-like receptors 2 and 4 (5I01BX003678-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9859331. Licensed CC0.

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