Survival-time dependent increase in neuronal IL-6 and astroglial GFAP expression in fatally injured human brain tissue

Abstract

Knowledge on trauma survival time prior to death following a lethal traumatic brain injury (TBI) may be essential for legal purposes. Immunohistochemistry studies might allow to narrow down this survival interval. The biomarkers interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) are well known in the clinical setting for their usability in TBI prediction. Here, both proteins were chosen in forensics to determine whether neuronal or glial expression in various brain regions may be associated with the cause of death and the survival time prior to death following TBI. IL-6 positive neurons, glial cells and GFAP positive astrocytes all concordantly increase with longer trauma survival time, with statistically significant changes being evident from three days post-TBI (p < 0.05) in the pericontusional zone, irrespective of its definite cortical localization. IL-6 staining in neurons increases significantly in the cerebellum after trauma, whereas increasing GFAP positivity is also detected in the cortex contralateral to the focal lesion. These systematic chronological changes in biomarkers of pericontusional neurons and glial cells allow for an estimation of trauma survival time. Higher numbers of IL-6 and GFAP-stained cells above threshold values in the pericontusional zone substantiate the existence of fatal traumatic changes in the brain with reasonable certainty. Published: xx xx xxxx open Scientific RepoRtS | (2019) 9:11771 | https://doi.org/10.1038/s41598-019-48145-wwww.nature.com/scientificreports www.nature.com/scientificreports/ and compared them to cardiovascular causes of death immunohistochemically and via immunofluorescence for interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP).IL-6 as a well-known cytokine is a small glycoprotein with a molecular weight less than 30 kDa 27 . It is predominantly expressed by neurons and glial cells in the CNS and mediates complex reactions such as the pro-inflammatory response 28 , but also has neuroprotective potential with trophic, anti-apoptotic and anti-inflammatory characteristics 29,30 . These contrary effects seem to depend on the local IL-6 concentration 31-33 , which increases under certain circumstances such as TBI, subarachnoid hemorrhage or CNS infection 27 . Given its initiator function of acute phase response, it is considered as an early TBI marker 34 . GFAP is one of the most-widely studied proteins in neuropathology. This protein is a type III intermediate filament involved in maintaining the blood brain barrier. GFAP also provides stability in the astrocytes throughout the CNS and is essential for reactive processes such as astrogliosis and glial scar formation 35 .Both IL-6 and GFAP are well-established biomarkers used in living patients with TBI to confirm and predict the existence and severity of the brain injuries and to determine the potential neurological outcome in trauma patients [36][37][38][39][40] . Furthermore, both markers are established for post-mortem biochemistry, with promising results for cerebrospinal fluid in...

TMEM119 as a specific marker of microglia reaction in traumatic brain injury in postmortem examination

“…Immunohistochemistry (IHC) has become an integral part of forensic histopathology over the last decades [4][5][6] and allows a more detailed approach in diagnosing and interpreting traumatic fatalities, when using biomarkers or proteins with high specificity to structures of the central nervous system (CNS) [7][8][9][10][11]. As additional tools in forensic neuropathological diagnosis, postmortem biochemical and immunocytochemical analyses of various cytokines, acute phase proteins, CNS biomarkers [8,[12][13][14][15][16], or Na + -glucose cotransporters [17] are Benjamin Ondruschka and Camelia-Maria Monoranu contributed equally to this work.…”

GFAP positivity in neurons following traumatic brain injuries

“…Traumatic brain injury (TBI) is defined as a chronic disease process [1] that contributes considerably to the global burden of injury [2]. Traumatic impact to the head causes glial, neuronal and axonal injuries followed by neuroinflammation and an activation of microglia [3][4][5]. The resulting brain damage and the subsequent recovery are indirectly reflected by an increase or decrease in intracellular proteins within brain tissue or other organic compounds within particular body fluids, which are, therefore, deemed as cerebral biomarkers [6].…”

“…The resulting brain damage and the subsequent recovery are indirectly reflected by an increase or decrease in intracellular proteins within brain tissue or other organic compounds within particular body fluids, which are, therefore, deemed as cerebral biomarkers [6]. Some common examples of TBI-related biomarkers are neuron-specific enolase, brain-derived neurotrophic factor, tau protein, neurofilament, myelin basic protein, S100 calcium-binding protein B (S100B), interleukin 6 (IL-6) and glial fibrillary acidic protein (GFAP) [3,5,[7][8][9][10][11].…”

Myelin basic protein and neurofilament H in postmortem cerebrospinal fluid as surrogate markers of fatal traumatic brain injury

“…In addition to forensic neuropathological diagnostic methods, Benjamin Ondruschka and Michael Bohnert contributed equally to this work. postmortem biochemical analyses of various cytokines, acute phase proteins, CNS biomarkers [7,[13][14][15][16][17], or Na + -glucose transporters [18] in CSF and brain tissue as well as investigations of the early tissue reaction of local microglia after trauma are meanwhile increasingly performed [19]. Furthermore, the applicability of immunocytochemical staining in postmortem CSF could be demonstrated [20].…”