# Rethinking the "quiet" nature of apoptotic cell clearance.

> **NIH NIH DP2** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $1,593,000

## Abstract

PROJECT SUMMARY
Each day billions of cells die and are cleared rapidly with minimal immunological consequence. This process,
clearance of apoptotic cells or efferocytosis, is carried out by phagocytes such as macrophages which are
numerically fewer in tissues and are often responsible for clearing multiple dead cells and debris in quick
succession. Efferocytosis is thought to be important for preventing autoimmunity and inflammatory disease.
However, patients suffering from autoimmunity or inflammatory disease rarely present with symptoms expected
from a defect in clearance of apoptotic cells, such as excessive accumulation of apoptotic or necrotic cells. On
one hand, you have a process that is occurring in every tissue and organ, yet on the other hand, it remains
unclear how this process contributes to or prevents autoimmunity and inflammatory disease. We present a new
model that suggests autoimmunity and inflammatory disease arise because of disruptions in how macrophages
manage apoptotic cell digestion instead of whether or not macrophages engulf at all. This model suggests that
efferocytosis is a dangerous process because the content of engulfed apoptotic cells, such as lipids, amino acids,
and nucleic acids, can trigger potentially catastrophic inflammatory responses by macrophages. To prevent this,
we hypothesize that macrophages use mechanisms to rapidly detect and respond to the engulfed material,
termed rapid response circuits (RRCs). This proposal combines novel experimentation with -omics approaches
and informatics to identify and assemble putative efferocytosis RRCs, then uses innovative tools and methods
to mechanistically study identified efferocytosis RRCs. Using this approach, we will first examine the common
efferocytosis RRCs used by macrophages. Then, we will explore unique efferocytosis RRCs used by tissue-
resident macrophages who are exposed to dying cells and debris specific to the tissue of residence. Collectively,
this work on RRCs will contribute to a new framework for understanding how failure to appropriately digest
apoptotic cells contributes to autoimmunity and inflammatory disease, and possibly reveal novel diagnostics and
therapeutics.

## Key facts

- **NIH application ID:** 10242446
- **Project number:** 1DP2GM146337-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Justin S Perry
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,593,000
- **Award type:** 1
- **Project period:** 2021-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242446

## Citation

> US National Institutes of Health, RePORTER application 10242446, Rethinking the "quiet" nature of apoptotic cell clearance. (1DP2GM146337-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242446. Licensed CC0.

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