# A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $378,750

## Abstract

Sepsis is a life-threatening condition that affects more than 1 million patients a year in the United States.
Growing evidence indicates that immunosuppression is a major driving force for mortality in sepsis.
Macrophages play essential roles in immune response to pathogens. Previous clinical studies have shown that
peripheral monocytes are depleted in septic patients through apoptosis. Recent in vitro studies revealed that
bacterial components, flagellin, the rod protein of the type III secretion system (T3SS), or LPS induce
pyroptosis of macrophages through activation of inflammasome pathways. In this proposal, we provide
convincing evidence that both peripheral monocytes and tissue macrophages are depleted due to pyroptosis in
mouse sepsis models including the cecal ligation and puncture (CLP) model. We show that intravenous
injection of flagellin or the rod proteins induced depletion of peripheral monocytes and macrophages in tissues.
We further demonstrate that depletion of these cells in mice impaired immune response and increased
mortality rate by subsequent challenged with E. coli. Importantly, our data indicate that tissue factor released
from pyroptotic monocytes and macrophages triggers disseminated intravascular coagulation (DIC). Thus, our
findings identified monocyte/macrophage depletion as a novel mechanism of immunosuppression and DIC in
sepsis. The goal of this application is to delineate the underlying mechanisms of monocyte/macrophage
depletion and its contribution to immunosuppression in sepsis. Aim 1 is to delineate the mechanisms of
pyroptotic monocyte and macrophage death during sepsis. The working hypothesis is that inflammasome
activation and subsequent pyroptosis play a critical role in monocyte/macrophage depletion during sepsis.
Mouse models deficient in caspase-1, caspase-11, caspase-1/11 double, or GSDMD (whole-body and
macrophage-specific) will be used to elucidate the detailed mechanism of inflammasome activation and
pyroptosis in monocyte/macrophage depletion. Aim 2 is to identify the mechanism by which rod protein and
flagellin induce pyroptosis leading to monocyte/macrophage depletion. We recently identified an intracellular
binding partner of EprJ, the acyl-CoA dehydrogenase family member type 9 (ACAD9) in macrophages. We will
use different approaches to test the hypothesis that the ACAD9-dependent pathway contributes to
macrophage depletion. Aim 3 is to identify the contribution of monocyte/macrophage depletion to
immunosuppression during sepsis. We will use a combination of sepsis models to investigate the role of
monocyte/macrophage depletion in immunosuppression during sepsis. Peripheral monocyte depletion in septic
patients will also be investigated. Completion of the proposed studies will reveal a novel molecular mechanism
of immunosuppression induced by Gram-negative bacteria. Such findings will significantly advance our
understanding about the pathogenesis of sepsis and identify new drug targets for thi...

## Key facts

- **NIH application ID:** 10436162
- **Project number:** 5R01GM132443-05
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** ZHENYU Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,750
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436162

## Citation

> US National Institutes of Health, RePORTER application 10436162, A novel mechanism of immunosuppression in sepsis: Depletion of monocytes and macrophages (5R01GM132443-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10436162. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*