# Macrophage Metabolism and Inflammation in Metabolic Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $343,125

## Abstract

ABSTRACT
Dysfunctional inflammatory and wound healing responses are clinically important complications of
diabetes, however the mechanisms underlying these defects remain elusive. Macrophages are cells of
the innate immune system that orchestrate inflammatory and reparative responses. Evidence is
emerging that macrophage dysfunction in diabetes contributes to inflammatory complications of this
disease, including poor healing of skin wounds. While the mechanisms of macrophage dysfunction in
diabetes are not well understood, it has recently become apparent that excess release of the cytokine IL-
1β promotes adverse wound healing. IL-1β release is regulated by the inflammasome, a pro-
inflammatory complex that cleaves and activates IL-1β. In diabetes, elevated levels of circulating lipids
promote macrophage lysosome damage and inflammasome activation; yet, the mechanistic links
between macrophage lipid handling and IL-1β release are unclear. At sites of inflammation,
macrophages undergo a shift in cellular metabolism towards fatty acid and mitochondrial oxidation
pathways, a process regulated in part by the nuclear receptor transcription factor PPARγ. We
hypothesize that when this metabolic shift occurs in the setting of excess lipid, macrophage lysosome
damage and inflammasome activation will be enhanced. The main objective of this proposal is to
determine how macrophage fatty acid metabolism contributes to inflammasome activation and poor
wound healing in diabetics and to leverage this knowledge for translational investigation. Our preliminary
studies demonstrate that PPARγ deficient macrophages have reduced rates of mitochondrial fatty acid
utilization and less IL-1β release in response to lipid-inflammatory stress. In Aim 1, the mechanistic link
between nutrient excess, mitochondrial lipid handling, and inflammasome activation will be dissected in
primary macrophages in vitro. Genetic and pharmacologic approaches in combination with metabolic
phenotyping, metabolomics analyses, and cell function assays will be employed. Aim 2 will then assess
diabetic skin wound healing in two genetic models of macrophage fatty acid oxidation deficiency to
address the in vivo links between macrophage lipid stress, inflammasome activation, and poor wound
healing. In Aim 3, the effects of pharmacologic modulators of lipid metabolism on diabetic wound healing
and inflammasome activation will be investigated. The results of these studies will be an important first
step in the long-term goal of this research program, which is to dissect the mechanisms by which nutrient
stress can impair macrophage inflammatory and reparative function in metabolic disease. The proposed
studies aim to elucidate novel molecular targets that alter the crosstalk between fatty acids, mitochondrial
oxidation and the inflammasome. This work is likely to have a strong positive impact on the field through
identification of new pathways relevant to the treatment of diabetic wound healing compli...

## Key facts

- **NIH application ID:** 9920593
- **Project number:** 5R01DK110034-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Joel David Schilling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,125
- **Award type:** 5
- **Project period:** 2016-06-15 → 2021-12-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920593

## Citation

> US National Institutes of Health, RePORTER application 9920593, Macrophage Metabolism and Inflammation in Metabolic Disease (5R01DK110034-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9920593. Licensed CC0.

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