Circulating mitochondrial DAMPs cause inflammatory responses to injury

Area of Science:

• Immunology
• Cellular Biology
• Trauma Research

Background:

• Systemic inflammatory response syndrome (SIRS) after injury resembles sepsis.
• Innate immunity is activated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
• Mitochondria, with bacterial origins, may release immune-activating molecules upon cellular injury.

Purpose of the Study:

• To investigate if injury releases mitochondrial DAMPs (MTDs).
• To determine the immune consequences of circulating MTDs.
• To explore the role of MTDs in linking trauma to SIRS.

Main Methods:

• Analysis of circulating factors released after injury.
• Activation assays using human polymorphonuclear neutrophils (PMNs) stimulated with MTDs (formyl peptides, mitochondrial DNA).
• Assessment of PMN responses including calcium flux, MAP kinase phosphorylation, migration, and degranulation in vitro and in vivo.

Main Results:

• Injury releases MTDs, including formyl peptides and mitochondrial DNA, into circulation.
• MTDs activate PMNs via formyl peptide receptor-1 and Toll-like receptor 9.
• MTDs promote PMN activation, migration, and degranulation, leading to organ injury.

Conclusions:

• Mitochondrial DAMPs released by cellular injury activate innate immunity through pathways similar to sepsis.
• MTDs act as endogenous danger signals, linking trauma to a sepsis-like inflammatory state.
• Mitochondria represent a critical source of 'enemies within' that exacerbate inflammation post-injury.