# A beneficial persistent DNA damage-induced immune response in aging

> **NIH NIH R56** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $709,654

## Abstract

PRIJECT SUMMARY/ABSTRACT
 The systemic immune effects of DNA damage in aging and disease remain elusive. It is generally
believed that immune responses triggered by transient DNA damage are beneficial while those associated with
persistent DNA damage are detrimental. We recently reported that NLRP12 (NOD-like receptor 12), a member
of the NLR inflammasome family that plays a central role in innate immunity, is induced by persistent DNA
damage, and that persistent DNA damage-induced NLRP12 improves the function of hematopoietic stem and
progenitor cells (HSPCs) in both mouse and human models of DNA repair deficiency and aging. These results
argue a protective role of NLRP12 in the context of immune response to persistent DNA damage under
conditions of DNA repair deficiency and aging.
 However, the mechanism underpinning the link between persistent DNA damage and NLRP12
expression in disease and aging has not been defined. To exploit this, we performed preliminary mechanistic
studies and found that persistent DNA damage induced abundant cytosolic dsDNA and consequently activation
of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in HSPCs from DNA
repair-deficient (Fanca-/-) and aged mice treated with ionizing radiation (IR) or the DNA cross-linker mitomycin C
(MMC). Concomitantly, a major transcription factor for Nlrp12, PU.1, was also elevated. We further showed that
inhibition of the cGAS-STING pathway PU.1 abolished persistent DNA damage-induced NLRP12 expression in
these damaged HSPCs, suggesting a potential link between the cGAS-STING pathway and persistent DNA
damage-induced NLRP12 expression. To further investigate this novel mechanistic link and its functional
implications, we generated a conditional Nlrp12 mouse model, with which we deleted the Nlrp12 gene specifically
in the hematopoietic lineages using the Vav1-Cre deleter strain. We observed exacerbated aging phenotypes in
Nlrp12-deficient Fanca-/- and aged mice, accompanied with the senescence associated secretory phenotype
(SASP) in the bone marrow (BM) and a significant increase in pyroptosis in BM HSPCs. Furthermore, deletion
of Nlrp12 significantly increased cytoplasmic localization of NLRP3, a hallmark of NLRP3 inflammasome
activation in the Nlrp12-deficient Fanca-/- and aged HSPCs. These preliminary studies suggest a novel interplay
between persistent DNA damage and immune response: cGAS-STING-mediated upregulation of NLRP12 as a
systemic pro-homeostatic effector of immune response to otherwise detrimental persistent DNA damage. We
hypothesize that persistent DNA damage activates a non-canonical cGAS-STING-PU.1 pathway to induce
the upregulation of NLRP12, which suppresses SASP to impede chronic inflammation and inhibits
NLRP3 inflammasome to prevent HSPC pyroptosis. The goals of the project are to investigate: (1) the
mechanisms linking persistent DNA damage to NLRP12 upregulation and (2) the functional links between
persistent DNA damage and u...

## Key facts

- **NIH application ID:** 11175787
- **Project number:** 1R56HL169348-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Wei Du
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $709,654
- **Award type:** 1
- **Project period:** 2024-09-17 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175787

## Citation

> US National Institutes of Health, RePORTER application 11175787, A beneficial persistent DNA damage-induced immune response in aging (1R56HL169348-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11175787. Licensed CC0.

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