# The role of cell type-specific necroptosis on chronic inflammation and cell non-autonomous effects on other tissues

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $145,000

## Abstract

Project Summary
Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is one of the ‘seven pillars of aging.
Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people and in a
variety of age-related diseases. Various tissues such as adipose tissue, muscle, brain, and liver have been
proposed to play a role in inflammaging, yet the pathway(s) responsible for inflammaging in a tissue or how
inflammaging in one tissue can impact other tissues is not known. In the current proposal, we will focus on liver
inflammaging. Liver macrophages are the major source of inflammation in the liver and they play a critical role
in the pathogenesis of age-related liver diseases, such as NASH. Damage-associated molecular patterns
(DAMPs, e.g., HMGB1) are major activators of macrophages and levels of DAMPs increase with age.
Necroptosis is a programmed cell death pathway that play a major role in inflammation through the generation
of DAMPs. In this proposal we will test the effect of hepatocyte-specific necroptosis on liver inflammation because
of the following reasons: (1) Our data show that necroptosis and inflammation increase with age in the liver (and
in hepatocytes) of wild type mice that is correlated with chronic liver disease (NASH). Inhibiting necroptosis using
necroptosis inhibitor, necrostatin-1s, reduced liver inflammation and NASH. (2) Our data show that necroptosis
can affect cell senescence, a pathway associated with aging and inflammation: i.e. inhibiting necroptosis reduced
markers of cell senescence in the livers of old mice. (3) There are data showing that inflammation associated
with chronic liver disease can cause detrimental effects in other tissues such as brain and skeletal muscle, two
key tissues associated with healthspan. Our preliminary studies show that over-expression of MLKL in
hepatocytes increases expression of proinflammatory cytokines in the liver and brain of young mice. The central
hypothesis of the supplement is that inducing necroptosis in one cell type will affect other cell types in that tissue
increasing inflammation in that tissue and will also have cell non-autonomous effects on other tissues. The
hypothesis will be tested using a novel knockin mouse model that will allow us to induce necroptosis specifically
in hepatocytes by conditionally overexpressing Mlkl, a key gene in necroptosis. Aim 1. To determine the effects
of hepatocyte necroptosis on liver; Aim 2. To determine the effect of hepatocyte necroptosis on the secretome;
Aim 3. To determine the non-autonomous effects of hepatocyte necroptosis on other tissues.

## Key facts

- **NIH application ID:** 10616037
- **Project number:** 3R01AG059718-04S1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Deepa Sathyaseelan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $145,000
- **Award type:** 3
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10616037

## Citation

> US National Institutes of Health, RePORTER application 10616037, The role of cell type-specific necroptosis on chronic inflammation and cell non-autonomous effects on other tissues (3R01AG059718-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10616037. Licensed CC0.

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