# Intracellular nucleic acid sensing and age-related chronic inflammation

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $481,840

## Abstract

Chronic inflammation is a common pathological basis for age-associated increases in autoimmunity,
diabetes, cancer, cardiovascular and Alzheimer’s disease as well as shortened lifespan. Failure to resolve
an activated innate immune response contributes significantly to chronic inflammation. Despite the profound
clinical implications, the specific innate pathways contributing to chronic inflammation remain unknown. We
reasoned that age-associated accrual of damaged DNA, which in other settings is a known driver of
inflammation through cell-intrinsic DNA-sensing pathways, may contribute to age-associated chronic
inflammation through these same innate pathways. Notably, cell-intrinsic DNA-sensing pathways require the
participation of the DNA-sensor, cGAS and ER-resident adaptor, STING and are potent inducers of the
pleiotropic cytokine family, type I interferons (IFN-I). IFN-I have been linked to chronic inflammation in
disorders such as autoimmunity and cancer. While the molecular components of age-associated chronic
inflammation remain undefined, a significant body of work suggests that recirculating innate cells may be
compromised, however, the contribution of tissue resident macrophages to aging has not been addressed.
Tissue macrophages are distinct from other myeloid-derived cells, not only in their origins, but also because
they integrate epigenetic and microenvironment cues to carry out a unique set of functions. In addition to
mounting innate immune responses, tissue macrophages are indispensable for tissue patterning, resolution
of inflammation and tissue repair. Here we propose to test the hypothesis that cytosolic DNA-sensing
promotes constitutive IFN-I induction within tissue macrophages and drives age-associated chronic
inflammation. We will systematically address how specific innate processes contribute to immune
dysfunction in the elderly in three specific aims. 1) We will evaluate the contribution of cytosolic DNA-sensing
pathways to aging-associated constitutive IFN-I and proinflammatory signatures in tissues and resident
macrophages using mice deficient in cGAS and STING. 2) We will determine the direct contribution cytosolic
DNA sensing pathways in exclusively shaping tissue macrophage fate and function with age by conditionally
deleting STING directly in tissue macrophage progenitors. As the epigenomes and transcriptomes of tissue
macrophages are highly plastic, we will utilize next generation sequencing to identify genome-wide changes
instigated by cytosolic DNA-sensing pathways in these cells with progressive age. 3) Finally, we will extend our
findings to humans and determine the baseline IFN-I signatures and responsiveness of tissue macrophages
from the lungs of geriatric patients and correlate them to well-represented loss-of-function haplotypes of STING.
By uncovering the molecular details of chronic inflammation in aging humans, the findings from this study offer
new immunomodulatory strategies and targets to bolster prot...

## Key facts

- **NIH application ID:** 9878744
- **Project number:** 5R01AI142005-02
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Shruti Sharma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,840
- **Award type:** 5
- **Project period:** 2019-02-22 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878744

## Citation

> US National Institutes of Health, RePORTER application 9878744, Intracellular nucleic acid sensing and age-related chronic inflammation (5R01AI142005-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878744. Licensed CC0.

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