Protein Citrullination: A Proposed Mechanism for Pathology in Traumatic Brain Injury

Abstract

Protein citrullination is a calcium-driven post-translational modification proposed to play a causative role in the neurodegenerative disorders of Alzheimer’s disease, multiple sclerosis (MS), and prion disease. Citrullination can result in the formation of antigenic epitopes that underlie pathogenic autoimmune responses. This phenomenon, which is best understood in rheumatoid arthritis, may play a role in the chronic dysfunction following traumatic brain injury (TBI). Despite substantial evidence of aberrations in calcium signaling following TBI, there is little understanding of how TBI alters citrullination in the brain. The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved. Immunofluorescence revealed that controlled cortical impact in rats profoundly up-­regulated protein citrullination in the cerebral cortex, external capsule, and hippocampus. This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia. Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins. Proteins most notably affected were those also reported to be citrullinated in other disorders, including prion disease and MS. In vivo findings were extended in an in vitro model of simulated TBI employing normal human astrocytes. Pharmacologically induced calcium excitotoxicity was shown to activate the citrullination and breakdown of glial fibrillary acidic protein, producing a novel candidate TBI biomarker and potential target for autoimmune recognition. In summary, these findings demonstrate that the effects of TBI on protein citrullination are selective with respect to brain region, cell type, and proteins modified, and may contribute to a role for autoimmune dysfunction in chronic pathology following TBI.

Putative Roles for Peptidylarginine Deiminases in COVID-19

“…A somewhat unsuspected comorbidity of COVID-19 is stroke [ 12 ]. PADs and deimination have indeed been recognised as a significant component in hypoxic ischaemic brain injury [ 25 , 26 ], as well as in traumatic and blast brain injury [ 114 , 115 ], and may contribute to autoimmune dysfunction in the chronic pathology following such events. The relationship between SARS-CoV-2 infection and stroke may be somewhat linked with the high vascular inflammatory reaction and vascular component seen in many COVID-19 cases, including also effects on pericytes [ 4 ], and therefore also with putative effects on the blood–brain barrier.…”

Peptidyl Arginine Deiminase 2 (PADI2)-Mediated Arginine Citrullination Modulates Transcription in Cancer

“…The responsible enzymes were later identified as Changes in citrullination occur in several pathological conditions such as autoimmune disorders and chronic inflammation-related diseases, including periodontitis, rheumatoid arthritis, atherosclerosis, and diabetes [13][14][15] (see Alghamdi, M. et al [13] for a detailed review on the intrinsic role of citrullination in autoimmune disorders and Olsen, I. et al, [14] for a detailed review on citrullination as a plausible link to periodontitis, rheumatoid arthritis, atherosclerosis, and Alzheimer's disease). Altered levels of citrullination have also been shown in neurological disorders and prion diseases, [16,17] and respiratory disorders [18,19]. Citrullination can generate new epitopes, which can produce new autoantigens linked to altered immune responses (see [20] for a review on citrullination and autoimmunity).…”

Peptidylarginine Deiminases as Mediators of Microvesicular Release - Novel Therapeutic Interventions

“…In two different mouse models of neonatal hypoxic ischaemic encephalopathy (HIE), firstly where permanent left carotid occlusion was followed with severe hypoxia (8% oxygen for 60 min), or secondly with 30 min hypoxia in combination with infection (as mimicked by LPS stimulation), one dose of Cl-Am (30 mg/kg) straight after hypoxia, or 10 min after LPS stimulation and again straight after hypoxia, significant reduction was observed in microglial activation, histone H3 deimination and cell death in all affected brain regions [33]. Interestingly, EV release has previously been associated with cerebral hypoxia induced by acute ischaemic stroke [93,94] while increased protein deimination has also been detected in the pathology of traumatic brain injury [95]. The fact that dampening of neuroinflammation and neuroprotective effects are achieved in vivo, using pharmacological PAD inhibition, and that this effect is translatable between CNS injury and animal models, is indeed promising for effective application also in other cases of neuronal damage.…”