Cerebrospinal Fluid Mitochondrial DNA

Abstract

Background Danger associated molecular patterns (DAMPs) are nuclear or cytoplasmic proteins that are released from the injured tissues and activate the innate immune system. Mitochondrial DNA (mtDNA) is a novel DAMP that is released into the extracellular milieu subsequent to cell death and injury. We hypothesized that cell death within the central nervous system in children with traumatic brain injury (TBI) would lead to release of mtDNA into the cerebrospinal fluid (CSF) and has the potential to predict the outcome after trauma. Methods CSF was collected from children with severe TBI that required intracranial pressure monitoring with Glasgow Coma Scale (GCS) scores ≤ 8 via an externalized ventricular drain. Control CSF was obtained in children without TBI or meningoencephalitis that demonstrated no leukocytes in the diagnostic lumbar puncture. Results The median age for patients with TBI was 6.3 y and 62% were male. The common mechanisms of injury included motor vehicle collision (35.8%) followed by falls (21.5%) and inflicted TBI (19%); 6 children (14.2%) died during their ICU course. The mean CSF mtDNA concentration was 1.10E +05 ± 2.07E+05 and 1.63E+03 ± 1.80E+03 copies/µL in the pediatric TBI and control population respectively. Furthermore, the mean CSF mtDNA concentration in pediatric patients who later died or had severe disability was significantly higher than that of the survivors (1.63E+ 05 ± 2.77E+05 vs. 5.05E+04 ± 6.21E+04 copies/µL) (p<0.0001). We found a significant correlation between CSF mtDNA and HMGB1, another prototypical DAMP, concentrations (ρ = 0.574, p<0.05), supporting the notion that both DAMPs are increased in the CSF following TBI. Conclusions Our data suggest that CSF mtDNA is novel DAMP in TBI, and appears to be a useful biomarker that correlates with neurological outcome after TBI. Further inquiry into the components of mtDNA that modulate the innate immune response will be helpful in understanding the mechanism of local and systemic inflammation after TBI.

The far-reaching scope of neuroinflammation after traumatic brain injury

“…50,51 Failure of mitophagy and resultant cell death can lead to release of mitochondrial DAMPs as reported for mitochondrial DNA after TBI in children. 52 These mitochondrial danger signals produce local and systemic responses by the interaction with receptors on immune cells: mitochondrial DNA by TLR9 on dendritic cells and N-formyl peptides by formyl peptide receptor-1 on neutrophils. 53 Membranes with mitochondrial cardiolipins on their surface are engulfed via cluster of differentiation 36 (CD36)-dependent phagocytosis.…”

Astrocyte roles in traumatic brain injury

“…In this regard, inhibition of NFκB signaling specifically in astrocytes reduces inflammation following CNS trauma (Brambilla et al, 2005; Brambilla et al, 2009). Additionally, increasing concentrations of the DAMPs HMGB1 and mitochondrial DNA in cerebrospinal fluid correlates with greater disability in TBI patients (Walko et al, 2014). However, NFκB signaling in astrocytes may also produce beneficial effects after brain injury, as it can result in their production and secretion of the neuro- and glioprotective growth factors, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) (Zaheer et al, 2001).…”

Clinical evidence of inflammation driving secondary brain injury

“…50 Elevated collections of proinflammatory cytokines may even predict depression. 51 The complexity of measuring multiple markers has motivated some investigators to create scores, assigning each marker a point value and evaluating an overall summation with clinically meaningful outcomes as a way of addressing this intricacy. 48 …”