# Role of GDF15 in the Regulation of Host Tolerance to Inflammation

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

PROJECT SUMMARY
Growth and Differentiation Factor 15 (GDF15) is highly induced in virtually all inflammatory conditions in
humans, including sepsis, cancer and autoimmunity, but its role in the inflammatory response has been
unclear. This proposal seeks to understand the role of Growth and Differentiation Factor 15 (GDF15) in
mediating protection in sepsis.
Preliminary data for this proposal reveals that GDF15 is induced specifically in models of acute
infection/inflammation but not other environmental stress conditions and achieves nanogram levels in
circulation. The GDF15 receptor, glial cell-lone derived neurotrophic factor receptor alpha-like (GFRAL), was
found only in the hindbrain and not induced by inflammation. Blockade of GDF15 led to enhanced mortality in
multiple models of sepsis, including lipopolysaccharide (LPS), cecal-ligation puncture (CLP), Poly(I:C), and
influenza. Conversely, late administration of recombinant GDF15 led to protection. GDF15 inhibition did not
affect inflammatory magnitude or pathogen control. However, GDF15 blockade led to an impairment in the
ability of mice to switch to an oxidative phosphorylation state. There was no difference in ketonemia or plasma
free fatty acids but a significant decrease in circulating plasma triglycerides. We also found that blockade of
GDF15 led to enhanced cardiotoxicity, without a difference in overall hemodynamic control. Thus, GDF15 is a
tissue protective hormone. This proposal seeks to test the idea that GDF15 is an adaptive cytokine produced
by macrophages in response to acute inflammation, which mediates cardioprotection by controlling triglyceride
metabolism via sympathetic innervation.

## Key facts

- **NIH application ID:** 10075879
- **Project number:** 5R01AI144152-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ruslan Medzhitov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075879

## Citation

> US National Institutes of Health, RePORTER application 10075879, Role of GDF15 in the Regulation of Host Tolerance to Inflammation (5R01AI144152-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10075879. Licensed CC0.

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