Microglial Inflammasome Activation in Penetrating Ballistic-Like Brain Injury

Abstract

Penetrating traumatic brain injury (PTBI) is a significant cause of death and disability in the United States. Inflammasomes are one of the key regulators of the interleukin (IL)-1β mediated inflammatory responses after traumatic brain injury. However, the contribution of inflammasome signaling after PTBI has not been determined. In this study, adult male Sprague-Dawley rats were subjected to sham procedures or penetrating ballistic-like brain injury (PBBI) and sacrificed at various time-points. Tissues were assessed by immunoblot analysis for expression of IL-1β, IL-18, and components of the inflammasome: apoptosis-associated speck-like protein containing a caspase-activation and recruitment domain (ASC), caspase-1, X-linked inhibitor of apoptosis protein (XIAP), nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3), and gasdermin-D (GSDMD). Specific cell types expressing inflammasome proteins also were evaluated immunohistochemically and assessed quantitatively. After PBBI, expression of IL-1β, IL-18, caspase-1, ASC, XIAP, and NLRP3 peaked around 48 h. Brain protein lysates from PTBI animals showed pyroptosome formation evidenced by ASC laddering, and also contained increased expression of GSDMD at 48 h after injury. ASC-positive immunoreactive neurons within the perilesional cortex were observed at 24 h. At 48 h, ASC expression was concentrated in morphologically activated cortical microglia. This expression of ASC in activated microglia persisted until 12 weeks following PBBI. This is the first report of inflammasome activation after PBBI. Our results demonstrate cell-specific patterns of inflammasome activation and pyroptosis predominantly in microglia, suggesting a sustained pro-inflammatory state following PBBI, thus offering a therapeutic target for this type of brain injury.

The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury

“…The activation of the inflammasome in perilesional neurons and microglia is one of the early events initiated after brain injury [72] and plays a role in the secondary injury mechanisms [73]. Therefore, the anti-inflammatory activity of tibolone, detected in BV-2 microglia [41], may be one of the mechanisms by which the steroid reduces gliosis and reduces secondary neuronal death.…”

Penetrating Ballistic-Like Brain Injury Leads to MicroRNA Dysregulation, BACE1 Upregulation, and Amyloid Precursor Protein Loss in Lesioned Rat Brain Tissues

“…-223 may occur as a consequence of microglial activation (Thounaojam et al, 2013;Lee et al, 2018) as well as posttraumatic mitochondrial injury, a novel therapeutic target for TBI (Wang et al, 2015;Harmon et al, 2017).…”

Targeting NLRP3 Inflammasome in the Treatment of CNS Diseases

“…For example, traumatic brain injury, a major cause of death and disability all over the world especially among children and teenagers, was considered to lead to the neuropathological conditions, which consequently cause the initiation of the production of the proinflammatory cytokines ( Mortezaee et al, 2017 ). The NLRP3 inflammasome has been demonstrated to play a pivotal role in the development of traumatic brain injury through several kinds of mechanisms including RIP3-related pathway, activation of cortical microglia and so on ( Lee et al, 2018b ; Liu et al, 2018 ). As a result, inhibiting the NLRP3 inflammasome in CNS serves as a potential and effective pathway for the attenuation of the development of traumatic brain injury.…”