# Mechanisms Regulating Inflammatory Phenotypes in Fetal Macrophages

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $395,215

## Abstract

Summary
Macrophages are among the earliest immune cells present during fetal development. Different populations of
macrophages have distinct functions, with early yolk sac derived macrophages having an immune tolerant
function and later liver derived macrophages having a more robust inflammatory profile. In the mouse lung, the
inflammatory profile of liver derived macrophages increases late in development and peaks around the time of
birth. This pro-inflammatory phenotype of fetal macrophages conflicts with previous notions that the fetal
immune system resides solely in a tolerant state. Inflammatory macrophages may function to protect the
developing fetus and newborn from pathogens encountered right at birth, but might also contribute to
inflammatory disease pathogenesis, particularly in infants born preterm. We hypothesize that newly formed
macrophages arising from the fetal liver are programmed for inflammation via the IKKb/NF-kB pathway.
However, once macrophages travel to various organs in the developing fetus, they may adopt tissue-specific
features. This proposal will use state of the art, complementary approaches to measure developmental
changes in the immune signature of fetal macrophages within developing mouse tissues. Experiments using
knockout mice will test if canonical IKKb/NF-kB signaling is required for the pro-inflammatory phenotype. While
the myelopoietic cytokine GM-CSF is known to promote alveolar macrophage differentiation in the lung after
birth, our preliminary data suggest it may also regulate the inflammatory phenotype in fetal lung macrophages.
Studies using Csf2 (the gene encoding GM-CSF) knockout mice will test the requirement of GM-CSF on the
developing lung immune system and specifically macrophages. The project will bring together experts in
developmental immunology and computational modeling and employ novel, cutting edge approaches to
complex systems immunology. The results generated by this proposal will fill a significant gap in our
understanding of the fetal immune system and the unique functional properties of macrophages protecting
newborns.

## Key facts

- **NIH application ID:** 10930057
- **Project number:** 5R01HD113215-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Lawrence S Prince
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,215
- **Award type:** 5
- **Project period:** 2023-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930057

## Citation

> US National Institutes of Health, RePORTER application 10930057, Mechanisms Regulating Inflammatory Phenotypes in Fetal Macrophages (5R01HD113215-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10930057. Licensed CC0.

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