# Regulation of the Microglial Neuroimmune Response by Long Non-Coding RNAs

> **NIH NIH R15** · CREIGHTON UNIVERSITY · 2022 · $436,468

## Abstract

PROJECT SUMMARY/ABSTRACT
 Systemic inflammation due to viral or bacterial infection is a direct cause of dysregulated neuroimmune
responses and is linked to several neurodegenerative pathologies such as multiple sclerosis (MS). Microglia
participate in innate immune processes of pathogen clearance contributing to both neurorecovery and
neurotoxicity. Proper microglial immune function supports neurogenesis and synapse development, regulates
homeostatic neuronal and glial activity, and provides host defense against pathogens and injury. Dysregulation
microglial immune function is likely to contribute to neuroinflammatory processes that cause neurotoxicity. The
mechanisms governing microglial functional plasticity and whether microglial immune responses are
neuroprotective or neurotoxic are not well understood. Long intergenic non-coding RNAs (lincRNAs) are
prime candidates for regulating microglial plasticity because many lincRNAs are early-primary response
genes whose expression is stimulated by environmental signals. LincRNAs are associated with human
inflammatory disease and neuropathologies such as MS. Our collaborative work has identified lincRNAs that
regulate pro-inflammatory gene expression in TLR4-stimulated macrophages and microglia through
modulation of chromatin remodeling. Based on these studies, we hypothesize that differential expression of
lincRNAs act as regulators of gene transcription to control microglial expression of neuroprotective or
neurotoxic phenotypes. Further, we propose that differential expression of lincRNAs will contribute to whether
microglial responses are effective in clearing pathogens and promoting normal function or causing
neurotoxicity and promoting neurodegeneration. To address this hypothesis, we mined whole-transcriptome
data and used an in vitro model system to identify lincRNAs that are inversely expressed in microglial pro-
inflammatory neurotoxic (TLR4-stimulated) and anti-inflammatory neurotrophic (IL-4-stimulated) functional
states. Our recently published work shows that lincRNAs are differentially expressed in microglial
neuroinflammatory and neurotrophic states and that silencing neuroinflammatory lincRNAs can reduce
neurotoxicity. Preliminary evidence shows that specific lincRNAs are overexpressed in degenerating cortical
tissue of a mouse model for progressive, chronic MS. The objectives of this proposal are to investigate the
mechanisms by which lincRNAs mediate a proinflammatory state in microglia (Aim 1) and to determine
whether differential lincRNA expression underlies viral-induced acute and chronic mouse models of MS (Aim
2). This proposal is conceptually innovative as it will provide information about lincRNA-regulated mechanisms
of neuroimmunity and neurotoxicity. These studies are directly applicable to the development of new
therapeutic strategies for limiting the neurodegeneration associated with inflammatory neuropathologies.

## Key facts

- **NIH application ID:** 10514892
- **Project number:** 1R15AI156879-01A1
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Annemarie Shibata
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $436,468
- **Award type:** 1
- **Project period:** 2022-07-14 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514892

## Citation

> US National Institutes of Health, RePORTER application 10514892, Regulation of the Microglial Neuroimmune Response by Long Non-Coding RNAs (1R15AI156879-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10514892. Licensed CC0.

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