# Regulation of microglial induced inflammation by non-canonical autophagy

> **NIH NIH F32** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $9,733

## Abstract

Project Summary
Recently, our laboratory identified a novel form of non-canonical autophagy where elements of the canonical
autophagy machinery conjugate LC3 to phagosomal membranes. As such, this process has been deemed
LC3-associated phagocytosis (LAP). Studies utilizing both cells and mice that are deficient in the LAP pathway
have shown that LAP is a mediator of macrophage polarization and inflammatory response. In the central
nervous system, microglial cells are the resident macrophage-like immune cells that are responsible for either
promoting or quenching inflammation. Like other macrophages, microglial cells can be immunologically
activated and polarized to either a pro-inflammatory M1-phenotype or an anti-inflammatory M2-phenotype. As
professional phagocytes and by virtue of a plethora of differing surface receptors, they are able to selectively
phagocytose target material including amyloid plaques that are a characteristic of most neurodegenerative
diseases. In the context of Alzheimer’s diseases (AD), recent evidence has demonstrated that amyloid
phagocytosis and activation of microglial cells promotes polarization towards the pro-inflammatory M1-state,
leading to pro-inflammatory cytokine production and subsequent neuroinflammation. Herein, we provide
preliminary evidence demonstrating that LAP promotes polarization of activated microglia to the anti-
inflammatory M2-phenotype. Moreover, we provide convincing evidence that the LAP mechanism is engaged
during phagocytosis of β-amyloid in microglial cells. We hypothesize that LAP is protective against
neuroinflammation by promoting anti-inflammatory polarization of microglial cells in response to β-amyloid.
Therefore, the experiments designed in the first aim of this proposal are directed at evaluating the molecular
mechanisms controlling cell polarization in response to β-amyloid in the presence or absence of LAP. The
second aim is designed to address the significance of microglial LAP to neuroinflammation in vivo. To achieve
this aim we will be using an established murine model of AD that replicates human disease. By exploring this
novel mechanism at both the molecular and physiological levels, we will develop a more comprehensive
understanding of how neuroinflammation is established and maintained during neurodegeneration. More
importantly, the studies proposed will provide new opportunities for manipulation and development of new
treatment methodologies.

## Key facts

- **NIH application ID:** 9970395
- **Project number:** 5F32AI138492-03
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Bradlee L Heckmann
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $9,733
- **Award type:** 5
- **Project period:** 2018-09-01 → 2020-09-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970395

## Citation

> US National Institutes of Health, RePORTER application 9970395, Regulation of microglial induced inflammation by non-canonical autophagy (5F32AI138492-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9970395. Licensed CC0.

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