# Suppression of Immune Signatures of Stress by Polyphenols Supplements

> **NIH NIH U19** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $450,144

## Abstract

Summary/Abstract 
The goal of Project 1 is to establish that a botanical supplement provides resilience against stress-induced 
pathophysiological responses that confer susceptibility to depressive behavior. This proposal will investigate 
how polyphenol metabolites of a bioactive dietary polyphenol preparation (BDPP) engage biomolecular and 
genetic targets in microglia, medium spiny neurons (MSNs), and blood brain barrier (BBB) cells to promote 
resilience of neuronal function and behavior in response to stress. Recent studies show that dysfunctional 
immune activity confers susceptibility to stress by affecting activity of these aforementioned cells. Systemic 
upregulation of inflammatory cytokines, in particular interleukin-6 (IL-6), by stress is observed in model 
systems of depression, as well as in patients with MDD. From preliminary studies involving a validated model 
of social stress, we show persistent IL-6 expression from leukocytes affects the BBB function only in stress- 
susceptible mice. We present evidence that BDPP bioavailable metabolites may promote resilience to social 
stress by suppressing production of cytokines, which is associated with maintenance of BBB integrity. Our first 
goal is therefore to establish if BDPP provides resilience against stress-induced depression by targeting 
mechanisms associated with BBB function. This aim will determine whether a botanical supplement prevents 
BBB permeability and infiltration of peripheral immune factors through the neuroendothelium, and will 
characterize biomolecular targets of BDPP metabolites in endothelial cells. Our preliminary studies show 
BDPP supplementation suppresses stress-induced microglia hyper-ramification and upregulation of 
inflammatory genes, which are associated with stress-susceptibility. Our second goal is to conduct an 
unbiased screen to identify molecular bioactivities of BDPP metabolites in microglia in response to stress. 
This aim involves a cell-specific RNA-sequencing technique termed translating ribosomal affinity purification 
(TRAP). Moreover, Aim 2 will characterize how increased activity of toll/nod-like receptors in microglia confer 
susceptibility to stress-induced depression, and act as proximate biological targets for BDPP metabolites. 
Finally, we show how BDPP metabolites prevent maladaptive glutamatergic synapse generation in the NAc in 
response to stress by regulating expression of synaptic genes in MSNs. We also show that peripheral IL-6 
production by peripheral leukocytes in response to stress is critical for facilitating aberrant synapse formation in 
the NAc. The final goal will therefore be to conduct an unbiased screen to identify molecular bioactivities of 
BDPP metabolites in D2 MSNs using the TRAP method and to investigate if peripheral IL-6 diffusion into the 
brain activates microglia via the IL-6R to effect regulation of NAc synapse densities. This would provide a 
mechanism for why suppression of peripheral IL-6 by a bot...

## Key facts

- **NIH application ID:** 10200686
- **Project number:** 5U19AT010835-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Giulio Maria Pasinetti
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,144
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200686

## Citation

> US National Institutes of Health, RePORTER application 10200686, Suppression of Immune Signatures of Stress by Polyphenols Supplements (5U19AT010835-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10200686. Licensed CC0.

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