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Complement mediates neuroinflammation and cognitive decline at extended chronic time points after traumatic brain injury.

ABSTRACT: Traumatic brain injury (TBI) can result in progressive cognitive decline occurring for years after the initial insult, and for which there is currently no pharmacological treatment. An ongoing chronic inflammatory response after TBI is thought to be an important factor in driving this cognitive decline. Here, we investigate the role of complement in neuroinflammation and cognitive decline for up to 6 months after murine TBI. Male C57BL/6 mice were subjected to open head injury using a controlled cortical impact device. At 2 months post TBI, mice were moved to large cages with an enriched environment to simulate rehabilitation therapy, and assigned to one of three treatment groups: 1. vehicle (PBS), 2. CR2Crry (3 doses over 1 week), 3. CR2Crry (continuous weekly dose until the end of the study). The study was terminated at 6 months post-TBI for all groups. Motor and cognitive function was analyzed, with histopathological analysis of brain tissue. Measured at 6 months after TBI, neither of the complement inhibition paradigms improved motor performance. However, mice receiving continuous CR2Crry treatment showed improved spatial learning and memory compared to both mice receiving only 3 doses and to mice receiving vehicle control. Analysis of brain sections at 6 months after injury revealed ongoing complement activation in the control group, with reduced complement activation and C3 deposition in the continuous CR2Crry treatment group. The ipsilateral hemisphere of continuously treated animals also showed a decrease in microglia/macrophage and astrocyte activation compared to vehicle. There was also increased astrocytosis in the contralateral hippocampus of vehicle treated vs. naïve mice, which was reduced in mice continuously treated with CR2Crry. This study demonstrates continued complement mediated neuroinflammation at extended chronic time points after TBI, and extends the potential treatment window for complement inhibition, which has previously been shown to improve outcomes after murine TBI.

SUBMITTER: Mallah K

PROVIDER: S-EPMC8056513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:We aimed to detect the possible accelerating role of previous traumatic brain injury (TBI) exposures on the onset of later cognitive decline assessed across different brain diseases. We analyzed data from the National Alzheimer's Coordinating Center (NACC), which provide information on history of TBI and longitudinal data on cognitive and non-cognitive domains for each available subject. At the time of this investigation, a total of 609 NACC subjects resulted to have a documented history of TBI. We compared subjects with and without a history of previous TBI (of any type) at the time of their first cognitive decline assessment, and termed them, respectively, TBI+ and TBI- subjects. Three hundred and sixty-one TBI+ subjects (229 male/132 female) and 248 TBI- subjects (156 male/92 female) were available. The analyses included TBI+ and TBI- subjects with a clinical diagnosis of Mild Cognitive Impairment, Alzheimer's disease, Dementia with Lewy bodies, Progressive supranuclear palsy, Corticobasal degeneration, Frontotemporal dementia, Vascular dementia, non-AD Impairment, and Parkinson's disease. The data showed that the mean age of TBI+ subjects was lower than TBI- subjects at the time of their first cognitive decline assessment (71.6 ± 11.2 vs. 74.8 ± 9.5 year; p < 0.001). Moreover, the earlier onset of cognitive decline in TBI+ vs. TBI- subjects was independent of sex, race, attained education, APOE genotype, and importantly, clinical diagnoses. As for specific cognitive aspects, MMSE, Trail Making Test part B and WAIS-R scores did not differ between TBI+ and TBI- subjects, whereas Trail Making Test part A (p = 0.013) and Boston Naming test (p = 0.008) did. In addition, data showed that neuropsychiatric symptoms [based on Neuropsychiatry Inventory (NPI)] were much more frequent in TBI+ vs. TBI- subjects, including AD and non-AD neurodegenerative conditions such as PD. These cross-sectional analyses outcomes from longitudinally-assessed cohorts of TBI+ subjects that is, subjects with TBI exposure before the onset of cognitive decline in the contest of different neurodegenerative disorders and associated pathogenetic mechanisms, are novel, and indicate that a previous TBI exposure may act as a significant "age-lowering" factor on the onset of cognitive decline in either AD and non-AD conditions independently of demographic factors, education, APOE genotype, and current or upcoming clinical conditions.

Project description:BACKGROUND:Understanding the interdependencies among inflammatory mediators of tissue damage following traumatic brain injury (TBI) is essential in providing effective, patient-specific care. Activated microglia and elevated concentrations of inflammatory signaling molecules reflect the complex cascades associated with acute neuroinflammation and are predictive of recovery after TBI. However, clinical TBI studies to date have not focused on modeling the dynamic temporal patterns of simultaneously evolving inflammatory mediators, which has potential in guiding the design of future immunomodulation intervention studies. METHODS:We derived a mathematical model consisting of ordinary differential equations (ODE) to represent interactions between pro- and anti-inflammatory cytokines, M1- and M2-like microglia, and central nervous system (CNS) tissue damage. We incorporated variables for several cytokines, interleukin (IL)-1?, IL-4, IL-10, and IL-12, known to have roles in microglial activation and phenotype differentiation. The model was fit to cerebrospinal fluid (CSF) cytokine data, collected during the first 5 days post-injury in n?=?89 adults with severe TBI. Ensembles of model fits were produced for three patient subgroups: (1) a favorable outcome group (GOS?=?4,5) and (2) an unfavorable outcome group (GOS?=?1,2,3) both with lower pro-inflammatory load, and (3) an unfavorable outcome group (GOS?=?1,2,3) with higher pro-inflammatory load. Differences in parameter distributions between subgroups were ranked using Bhattacharyya metrics to identify mechanistic differences underlying the neuroinflammatory patterns of patient groups with different TBI outcomes. RESULTS:Optimal model fits to data showed different microglial and damage responses by patient subgroup. Upon comparison of model parameter distributions, unfavorable outcome groups were characterized by either a prolonged, pathophysiological or a transient, sub-physiological course of neuroinflammation. CONCLUSION:By developing a mathematical characterization of inflammatory processes informed by clinical data, we have created a system for exploring links between acute neuroinflammatory components and patient outcome in severe TBI.

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Complement mediates neuroinflammation and cognitive decline at extended chronic time points after traumatic brain injury.

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