Minh-Nguyet Hoang

Background: Traumatic brain injury (TBI) is a multifactorial condition caused by an external mechanical force that can lead to various neurological impairments, including physical, psychological, and cognitive functions^1,3,4. TBIs represent the third most common cause of mortality worldwide, with an increased risk in the elderly, athletes, and low socioeconomic areas^{1, 2,3}. The primary injury causing TBI can lead to local brain damage and neuroinflammation, which can cause secondary damage and result in long-term neurological and physiological deficits^1,2,5,7,11. One neuroinflammatory pathway activated following TBI is the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, composed of three components: NLRP3, adapter protein apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1^10,13. Activation of this inflammasome complex by cleaved caspase-1 triggers increased secretion of interleukin-1β and interleukin-18, leading to pyroptosis in some neurons and glia. Hyperactivation by interleukins of downstream inflammatory pathways, including p38/MAPK signaling, can be detrimental to brain function^10,13. Diagnosis is based on neuroimaging, loss of consciousness, posttraumatic amnesia, and the Glasgow Coma Score^5,8. Current treatments aim to manage symptoms or complications through pharmacotherapy, cognitive therapy, and surgery^1,3,4. However, most potential therapeutic drugs are in Phase II of testing, with few targeting the mechanistic immune response pathways following TBI, presenting a significant gap for research^1,12.

Objective: This narrative describes the results of a study that explored a mechanistic treatment for TBI by inhibiting the NLRR3 inflammasome response in microglia, leading to improvements in acute and chronic symptoms post-TBI.

Search Methods: An online PubMed search was conducted from 2018 to 2023 using keywords: “traumatic brain injury”, “neuroinflammation”, “microglia”, and “NLRP3 inflammasome”.

Results: Microglia are activated following TBI, triggering the activation of NLRP3 inflammasomes^5,6,9,10. Chronic activation of microglia and neuroinflammation can result in acute and chronic complications, such as edema, mood change, and cognition^10,12. By eliminating activated microglia following TBI, the components of the NLRP3 inflammasome complex and the downstream IL-1β and IL-18 were reduced, leading to decreased neuroinflammation^10,12. The efficacy of extracellular vesicles derived from human mesenchymal stem cells (hMSC-EVs), naturally enriched with microglia-modulating miRNAs, was also examined in a mouse model following TBI¹². After a single intranasal dose, the hMSC-EVs were incorporated into microglia throughout injured brain regions, resulting in acute and chronic improvements in TBI mice¹². In the acute phase following TBI, there was a marked increase in concentrations of the NLRP3 inflammasome complex and corresponding interleukins, which decreased with the administration of the hMSC-EVs¹².  Administration of the hMSC-EVs was also shown to reduce chronic neuroinflammatory cascades following TBI, including cognitive and mood improvements¹².

Conclusion: Elimination or inhibition of activated microglia following TBI reduces acute and chronic adverse outcomes of TBI in adult mice by inhibiting the NLRP3 inflammasome complex mediators and downstream cytokines. Specifically, intranasal administration of hMSC-EVs enriched with microglia-modulating miRNAs effectively prevented the common secondary injuries in TBI. Further investigation into the therapeutic window, optimal dosage, and clinical trials studying the administration of hMSC-EVs following TBI are necessary before translation into medical practice. Overall, hMSC-EV-mediated microglial modulation presents a promising treatment for the acute and chronic complications of TBI.

Works Cited:

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8. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Committee on the Review of the Department of Veterans Affairs Examinations for Traumatic Brain Injury. Evaluation of the Disability Determination Process for Traumatic Brain Injury in Veterans. Washington (DC): National Academies Press (US); 2019 Apr 10. 2, Diagnosis and Assessment of Traumatic Brain Injury. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542595/
9. Witcher KG, Bray CE, Chunchai T, et al. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci. 2021;41(7):1597-1616. doi:10.1523/JNEUROSCI.2469-20.2020
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12. Kodali M, Madhu LN, Reger RL, et al. Intranasally administered human MSC-derived extracellular vesicles inhibit NLRP3-p38/MAPK signaling after TBI and prevent chronic brain dysfunction. Brain Behav Immun. 2023;108:118-134. doi:10.1016/j.bbi.2022.11.014
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