Expression of the NLRP3 Inflammasome in Cerebral Cortex After Traumatic Brain Injury in a Rat Model

Abstract

Inflammatory response plays an important role in the pathogenesis of secondary damage after traumatic brain injury (TBI). The inflammasome is a multiprotein complex involved in innate immunity and a number of studies have suggested that the inflammasome plays a critical role in a host inflammatory signaling. Nucleotide-binding domain, leucine-rich repeat, pyrin domain containing 3 (NLRP3) is a key component of the NLRP3-inflammasome, which also includes apoptotic speck-containing protein (ASC) with a cysteine protease (caspase)-activating recruitment domain and pro-caspase1. Activation of the NLRP3-inflammasome causes the processing and release of the interleukin 1 beta (IL-1β) and interleukin 18 (IL-18). Based on this, we hypothesized that the NLRP3-inflammasome could participate in the inflammatory response following TBI. However, the expression of NLRP3-inflammasome in cerebral cortex after TBI is not well known. Rats were randomly divided into control, sham and TBI groups (including 6 h, 1 day, 3 day and 7 day sub-group). TBI model was induced, and animals were sacrificed at each time point respectively. The expression of NLRP3-inflammasome was measured by quantitative real-time polymerase chain reaction, western blot and immunohistochemistry respectively. Immunofluorescent double labeling was performed to identify the cell types of NLRP3-inflammasome's expression. Moreover, enzyme linked immunosorbent assay was used to detect the alterations of IL-1β and IL-18 at each time point post-injury. The results showed that, TBI could induce assembly of NLRP3-inflammasome complex, increased expression of ASC, activation of caspase1, and processing of IL-1β and IL-18. These results suggested that NLRP3-inflammasome might play an important role in the inflammation induced by TBI and could be a target for TBI therapy.

Effects of Hyperbaric Oxygen Therapy on Inflammasome Signaling after Traumatic Brain Injury

“…As previously reported [6], we observed that the level of IL-1β in the brain parenchyma reached a peak on day 3 and decreased until day 7 after brain injury.…”

“…Acute elevation of inflammasome proteins, such as ASC, Casp-1 and NLRP1, has been found in the cerebrospinal fluid of TBI patients, and the degree of elevation correlates significantly with the long-term functional outcome [7]. The activation of the NLRP3 inflammasome has been observed in the inflammatory process of TBI [6]. Furthermore, when cocultured with cerebrospinal fluid from TBI patients, neurons show a significant increase in the levels of AIM2 and cleaved Casp-1 [5].…”

“…In particular, the inflammasomes, NOD (nucleotide-binding oligomerization domain)-like receptor (NLR) pyrin-domain-containing 1 (NLRP1), NLRP2, NLRP3 and absent in melanoma 2 (AIM2), are expressed abundantly in the brain and immune cells. These components play an important role in detecting cellular damage and mediating inflammatory responses during TBI [5,6,7]. …”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…NLRP3 inlammasomes were found in astrocytes, microglia and cortical neurons in a weightdrop model of TBI in rats [54]. Protein levels of NLRP3, active caspase-1, and IL-18 all gradually increased over the course of 7 days in cortical tissue ipsilateral to the contusion, while levels of IL-1β rose at 6 h post-injury and declined over the course of 7 days to sham levels [54]. In support of the role of NLRP3 in TBI, another animal study showed that the expression of NLRP3, caspase-1, and thioredoxin-interacting protein (TXNIP), a regulator of NLRP3 activity, were all increased in the cerebral cortex of rats at 12 and 24 h post-blast injury [55].…”

“…The NLRP1 inlammasome can additionally recruit various cell molecular responses including the membrane channel pannexin-1, the X-linked inhibitor of apoptosis protein (XIAP), caspase-5, caspase-11, and P2X purinoreceptor 7 to guide its activation and actions in various cell types [50]. NLRP3 inlammasomes were found in astrocytes, microglia and cortical neurons in a weightdrop model of TBI in rats [54]. Protein levels of NLRP3, active caspase-1, and IL-18 all gradually increased over the course of 7 days in cortical tissue ipsilateral to the contusion, while levels of IL-1β rose at 6 h post-injury and declined over the course of 7 days to sham levels [54].…”