# Inflammasome Activation Triggers Systemic Coagulation in Sepsis

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $429,469

## Abstract

Abstract
Septic shock is invariably associated with systemic coagulation leading to thrombus formation. Sepsis-related
organ dysfunction has been attributed to microvascular thrombosis. Mortality rate doubles in septic patients
with disseminated intravascular coagulation (DIC). DIC is even considered as a sign that “death is coming”.
Previous studies have demonstrated the important roles of tissue factor (TF) in sepsis-associated DIC.
However, the mechanism leading to TF release, which triggers systemic coagulation in sepsis, is unknown.
Recent in vitro studies revealed that bacterial components (flagellin, the rod protein of the type III secretion
system (T3SS), or LPS) induce programmed cell death (called pyroptosis) of macrophages through activation
of inflammasome pathways. We show that intravenous injection of a T3SS rod protein E. coli, EprJ, induced
depletion of peripheral monocytes and macrophages in tissues. Importantly, injection of EprJ or LPS, which
elicit canonical and noncanonical inflammasome activation, respectively, induced systemic coagulation
activation, as evident by prolonged prothrombin time (PT) due to increased consumption of coagulation factors,
thrombocytopenia, increased plasma levels of thrombin-antithrombin complex (TAT), and reduced plasma
fibrinogen levels. Thus, our findings made connections between the in vitro and in vivo observations and
suggested monocyte/macrophage pyroptosis as a trigger of DIC in sepsis. The goal of this application is to
delineate the underlying mechanisms by which inflammasome activation and pyroptosis trigger DIC in sepsis.
Specific Aim 1 will establish inflammasome activation and pyroptosis as a common mechanism for DIC
induced by bacterial infection. The working hypothesis is that bacteria and bacterial components from different
strains elicit DIC through Inflammasome activation and pyroptosis. We will use a combination of various
deficient mice to elucidate the role of inflammasome activation and pyroptosis in DIC elicited by Gram-negative
bacteria. Specific Aim 2 is to identify the molecular mechanism of TF release from macrophages following
inflammasome activation. We will also use the myeloid-specific TF knockout mice and a low TF mouse model
to elucidate whether DIC elicited by the bacterial components depends on release of TF from macrophages.
Specific Aim 3 will demonstrate the role of inflammasome activation in sepsis-associated coagulopathy. We will
use the cecal ligation and puncture (CLP) sepsis model and bacterial infusion sepsis model to investigate the
role of inflammasome activation and pyroptosis in coagulation. Completion of the proposed studies will
demonstrate the molecular mechanism of systemic coagulation is sepsis. Such findings would have profound
ramifications for the identification of new drug targets for DIC, the deadly complication of sepsis.

## Key facts

- **NIH application ID:** 10645452
- **Project number:** 7R01HL142640-04
- **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:** $429,469
- **Award type:** 7
- **Project period:** 2022-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10645452

## Citation

> US National Institutes of Health, RePORTER application 10645452, Inflammasome Activation Triggers Systemic Coagulation in Sepsis (7R01HL142640-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10645452. Licensed CC0.

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