Mitochondrial DAMPs Induce Endotoxin Tolerance in Human Monocytes: An Observation in Patients with Myocardial Infarction

Abstract

Monocyte exposure to mitochondrial Danger Associated Molecular Patterns (DAMPs), including mitochondrial DNA (mtDNA), induces a transient state in which these cells are refractory to further endotoxin stimulation. In this context, IRAK-M up-regulation and impaired p65 activity were observed. This phenomenon, termed endotoxin tolerance (ET), is characterized by decreased production of cytokines in response to the pro-inflammatory stimulus. We also show that monocytes isolated from patients with myocardial infarction (MI) exhibited high levels of circulating mtDNA, which correlated with ET status. Moreover, a significant incidence of infection was observed in those patients with a strong tolerant phenotype. The present data extend our current understanding of the implications of endotoxin tolerance. Furthermore, our data suggest that the levels of mitochondrial antigens in plasma, such as plasma mtDNA, should be useful as a marker of increased risk of susceptibility to nosocomial infections in MI and in other pathologies involving tissue damage.

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

“…In most cases, ET is associated with previous endotoxin contact, which induces a refractory state during a second endotoxin challenge (56,57). However, we also reported this phenomenon in "sterile" pathologies, such as myocardial infarction; mitochondrial DNA induce a manifest refractoriness in these patients (58).…”

NFκB2/p100 Is a Key Factor for Endotoxin Tolerance in Human Monocytes: A Demonstration Using Primary Human Monocytes from Patients with Sepsis

“…Circulating cells isolated from patients with sepsis show a reduced capacity to produce proinflammatory cytokines when stimulated with an endotoxin ex vivo (3,4). ET has also been observed for other pathologies such as acute coronary syndrome (5) and cystic fibrosis (6)(7)(8).…”

“…Real-time quantitative PCRs were performed using the QuantiMix Easy SYG kit from Biotools and specific primers. Results were normalized to the expression of the b-actin (actin), and the cDNA copy number of each gene of interest was determined using a 7-point standard curve, as described previously (4,5,7,20,21).…”

Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns

“…Intact mitochondria purified from necrotic cells are engulfed by human monocyte-derived macrophages and induce the production of pro-inflammatory cytokines (12). When injured, mitochondria can release into the circulation various intra-mitochondrial components such as mtDNA (35), formylated peptides (35), and ATP (36), all of which are recognized by PRRs of the immune systems and act as DAMPs (37,38). mtDNA can also be detected in transfusion blood and may contribute to transfusion-related acute lung injury (39).…”