# Macrophage Metabolism After Target Cell Ingestion Regulates Anti-Inflammatory Reprogramming

> **NIH NIH R00** · NATIONAL JEWISH HEALTH · 2021 · $249,000

## Abstract

ABSTRACT
 Inflammation is a ubiquitous component of lung disease involving accumulation of leukocytes in the
airspaces. In order for inflammation to resolve, dead and dying leukocytes must be removed and production of
inflammatory cytokines must be turned off. Macrophages (Mϕ) are key orchestrators of these processes,
however the triggers that reprogram inflammatory Mϕ to perform these roles remain incompletely understood.
Clearance of dead cells has been shown to provide an important reprogramming signal, but we have limited
knowledge of the precise mechanisms by which dead cell ingestion facilitates redirection of Mϕ function.
Recent work has demonstrated a key role for cellular metabolism in determining Mϕ function. Ingested target
cells provide a clear source of varied macromolecules that must be digested by Mϕ. However, little research
has been done to assess intracellular metabolites produced by this process or to consider the subsequent
immune consequence.
 We propose the first comprehensive study of Mϕ metabolism following target cell ingestion and
degradation, and hypothesize that changes in the levels of intracellular metabolites control ingestion-driven Mϕ
reprogramming. Our preliminary studies have identified a promising molecular target, polyamines, which are
dramatically increased in Mϕ following the ingestion of apoptotic target cells. Polyamines have a known anti-
inflammatory function including suppression of numerous pro-inflammatory cytokines. We propose to test the
hypothesis that upregulation of polyamine synthesis by Mϕ following target cell ingestion is critical to suppress
a key Mϕ cytokine IL-1β, and important for the resolution of lung inflammation in vivo.
 During the K99 mentored phase, I will build upon my experience studying Mϕ biology and target cell
clearance by learning techniques related to cellular metabolism including unbiased metabolomics and the use
of isotope metabolites to measure metabolic flux. During this phase, I will: 1) complete a comprehensive,
integrated assessment of the metabolites produced following ingestion of target cells, focusing on polyamines,
and assess whether these metabolites derive from digested target cell material, and 2) specifically assess the
role of arginase-1 in regulating polyamine synthesis by inflammatory Mϕ. Simultaneously, I will enrich my
professional development by participating in journal clubs, seminars, national conferences, coursework, and
having semi-annual evaluations by a trainee advisory committee. The R00 independent phase will allow me to
establish my laboratory as I continue investigation into: 3) how Mϕ polyamines affect cytokine production after
target cell ingestion, and 4) the effects of Mϕ polyamines on resolution of inflammation and lung repair.
Collectively, this proposal will enhance my current expertise, address a critical unknown in the field of target
cell clearance, and provide the necessary foundation to establish myself as an independent research ...

## Key facts

- **NIH application ID:** 10239261
- **Project number:** 5R00HL141658-04
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Alexandra Leigh McCubbrey
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10239261

## Citation

> US National Institutes of Health, RePORTER application 10239261, Macrophage Metabolism After Target Cell Ingestion Regulates Anti-Inflammatory Reprogramming (5R00HL141658-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10239261. Licensed CC0.

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