# Molecular regulation of TLR2-mediated autoimmune inflammation

> **NIH NIH R01** · ROSALIND FRANKLIN UNIV OF MEDICINE & SCI · 2020 · $390,000

## Abstract

SUMMARY
 The mechanisms governing CD4+ T cell activation and function in autoimmune disease remain insufficiently
understood even though autoreactive CD4+ T cells are central orchestrators for the initiation and progression of virtually
all autoimmune diseases. Multiple sclerosis (MS), a demyelinating disease of the central nervous system (CNS), is a well
characterized example of how the failure to control autoreactive CD4+ T cells can lead to devastating inflammation and
tissue damage. Encephalitogenic CD4+ T helper (Th) cells, especially Th17 and Th1 cells, promote CNS inflammation by
responding to self-antigens both in MS and the murine MS model, experimental autoimmune encephalomyelitis (EAE).
Our seminal work has identified an innate-like receptor with critical roles in driving the pathogenicity of encephalitogenic
Th17 cells in vivo. Since, we have further identified key transcriptional and epigenetic mechanisms associated with this
pathway, indicating that innate-like signaling drives signature programming events that render Th17 cells altogether more
pathogenic for autoimmune inflammation. Our preliminary work presented herein demonstrates that activation of this
pathway amplifies gene-promoting chromatin modifications at Th17-related loci, likely resulting in increased access for
pro-inflammatory transcription factors as well as the binding of a novel chromatin regulatory factor. This chromatin
regulator was recently characterized by our laboratory and we demonstrate its essentiality in mediating Th17 cell-
dependent autoimmune inflammation. Finally, our data demonstrates that endogenous ligands are potent amplifiers of this
pathway as well as encephalitogenicity in Th17 cells. Taken together, these novel results suggest that autoimmune
disorders may be treated through targeting the downstream effects of this pathway to inhibit Th17 cells. Therefore, the
goal of these studies is to characterize the mechanisms responsible for the increased inflammatory potential that we have
firmly established in these Th17 cells. Transcriptional, epigenetic, and functional analyses will be performed to tease out
the contributions of the novel regulatory factors identified by our preliminary work. Consequently, our project is designed
to test our central hypothesis through two interlinked specific aims.

## Key facts

- **NIH application ID:** 9823855
- **Project number:** 5R01AI141596-02
- **Recipient organization:** ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
- **Principal Investigator:** Joseph Michael Reynolds
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2018-11-15 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823855

## Citation

> US National Institutes of Health, RePORTER application 9823855, Molecular regulation of TLR2-mediated autoimmune inflammation (5R01AI141596-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9823855. Licensed CC0.

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