Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study

Abstract

Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

Transcriptional Pathology Evolves over Time in Rat Hippocampus after Lateral Fluid Percussion Traumatic Brain Injury

“…Studies that looked at later time points than this effort using similar rodent TBI models report that persistent immune and inflammation signatures that overlap with modules identified here last up to 2 years post injury, 60 and that this is, at least in part, attributable to microglial transition to a persistent altered inflammatory state. 61 , 78 Some of these long-term immune and inflammation transcriptional signatures can also be modulated by drug treatment.…”

“…Our findings are also in line with a study that used NanoString to profile candidate genes, finding differences in trajectories of sets of immune and inflammation genes, as well as decreased and shorter persistence of downregulation signatures post-TBI. 60 …”

“… 61 , 78 Some of these long-term immune and inflammation transcriptional signatures can also be modulated by drug treatment. 60 , 62 The genes and modules identified by our approach capture molecular mechanisms and represent new potential biomarkers for stage and biological pathway-specific components of recovery and lasting pathology post-TBI. Further, future studies evaluating the intersection between neurodegeneration, neuroinflammation, and neurotransmission over time may provide better insight into why behavior and, in particular, cognition shows some recovery over time, but perhaps not quite to an equivalent performance as an age-matched control.…”

Contralateral structure and molecular changes after severe unilateral brain injury

“…(Todd et al, 2021) Moreover, genes belonging to the complement system, such as C2, C3, and C4, were continuously upregulated during the chronic period in the ipsilateral hemisphere. (Toutonji et al, 2021) Many previous studies have used the contralateral hemisphere as the comparison when studying the effects of brain injury on the injured side; however, with the development of omics technology, the effects of trauma on the contralateral hemisphere raise concerns. White et al (White et al, 2013) reported an acute inflammatory gene response in the contralateral hemisphere after unilateral controlled cortical impact in rats that occurred despite the absence of activated inflammatory cells and suppression of the major inflammatory genes could prevent the progression of injury.…”

Traumatic brain injury: Mechanisms, manifestations, and visual sequelae

“…Parry and colleagues found that formation of a specific component of the complement system, soluble membrane attack complex C5b-9 (sC5b-9), was elevated in TBI and may be involved in secondary injury and death of neurons (Parry et al, 2020). Toutonji et al (2021) characterized the expression of 59 complement genes at different time points post-TBI and demonstrated an upregulated gene expression across most complement activation and effector pathways. The study found continued upregulation of C2, C3, and C4 expression up to 2 years following injury.…”