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Published on: February 12, 2016
Circulating Monocytes Exhibit an Endotoxin Tolerance Status after Acute Ischemic Stroke: Mitochondrial DNA as a
Enrique Hernández-Jiménez1,2,3, María Gutierrez-Fernández4, Carolina Cubillos-Zapata1,2,3
1Tumor Immunology Laboratory, Hospital La Paz Institute for Health Research, La Paz University Hospital, 28046 Madrid, Spain.
Abstract:
Patients with acute ischemic stroke (AIS) suffer from infections associated with mortality. The relevance of the innate immune system, and monocytes in particular, has emerged as an important factor in the evolution of these infections. The study enrolled 14 patients with AIS, without previous treatment, and 10 healthy controls. In the present study, we show that monocytes from patients with AIS exhibit a refractory state or endotoxin tolerance. The patients were unable to orchestrate an inflammatory response against LPS and expressed three factors reported to control the evolution of human monocytes into a refractory state: IL-1R-associated kinase-M, NFkB2/p100, and hypoxia-inducible factor-1α. The levels of circulating mitochondrial DNA (mtDNA) in patients with AIS correlated with impaired inflammatory response of isolated monocytes. Interestingly, the patients could be classified into two groups: those who were infected and those who were not, according to circulating mtDNA levels. This finding was validated in an independent cohort of 23 patients with AIS. Additionally, monocytes from healthy controls, cultured in the presence of both sera from patients and mtDNA, reproduced a refractory state after endotoxin challenge. This effect was negated by either a TLR9 antagonist or DNase treatment. The present data further extend our understanding of endotoxin tolerance implications in AIS. A putative role of mtDNA as a new biomarker of stroke-associated infections, and thus a clinical target for preventing poststroke infection, has also been identified.
Insights
Patients with acute ischemic stroke (AIS) show impaired monocyte inflammatory responses, a state known as endotoxin tolerance. Circulating mitochondrial DNA (mtDNA) levels may indicate infection risk in AIS patients.
Area of Science:
- Immunology
- Neurology
- Molecular Biology
Background:
- Infections are a significant cause of mortality in acute ischemic stroke (AIS) patients.
- The innate immune system, particularly monocytes, plays a crucial role in managing infections.
- Understanding immune dysregulation in AIS is vital for improving patient outcomes.
Purpose of the Study:
- To investigate the inflammatory response of monocytes in AIS patients.
- To identify factors contributing to immune dysfunction in AIS.
- To explore the potential of mitochondrial DNA (mtDNA) as a biomarker for infection in AIS.
Main Methods:
- Enrolled 14 AIS patients and 10 healthy controls.
- Assessed monocyte inflammatory response to lipopolysaccharide (LPS).
- Measured levels of IL-1R-associated kinase-M, NFkB2/p100, hypoxia-inducible factor-1α, and circulating mtDNA.
- Validated findings in an independent cohort of 23 AIS patients.
Main Results:
- Monocytes from AIS patients exhibited endotoxin tolerance, with impaired inflammatory response to LPS.
- Elevated circulating mtDNA levels in AIS patients correlated with reduced monocyte inflammatory capacity.
- AIS patients with higher mtDNA levels were more likely to be infected.
- mtDNA and AIS patient serum induced endotoxin tolerance in healthy control monocytes, inhibited by TLR9 antagonist or DNase.
Conclusions:
- AIS patients display endotoxin tolerance in their monocytes.
- Circulating mtDNA may serve as a biomarker for identifying AIS patients at risk of infection.
- Targeting mtDNA could be a potential strategy for preventing post-stroke infections.
