Abstract
As one of the most common causes of mortality and disability, traumatic brain injury (TBI) is a huge psychological and economic burden to patients, families, and societies worldwide. Neuroinflammation reduction may be a favorable option to alleviate secondary brain injuries and ameliorate the outcome of TBI. The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome, has been shown to be involved in TBI. NIMA-related kinase 7 (NEK7) has been verified as an essential mediator of NLRP3 inflammasome activation that is recruited upstream of the formation of inflammasomes in response to NLRP3 activators. However, the underlying mechanism by which NEK7 operates post-TBI remains undefined. In this study, we performed both in vivo and in vitro experiments. Using an in vivo mouse TBI model, mice were administered an intracerebroventricular injection of NEK7-shRNA virus. For the in vitro analysis, primary cortical neurons with NEK7-shRNA were stimulated with lipopolysaccharide (LPS)/ATP or potassium (K+). We evaluated the effects of NEK7 knock-down on neurological deficits, NLRP3 inflammasomes, caspase-1 activation, and neuronal injury. During the 0–168 h post-TBI period in vivo, NEK7 and NLRP3 inflammasome activation increased in what appeared to be a time-dependent manner. As well as pyroptosis-related markers, caspase-1 activation (p20) and interleukin-1β (IL-1β) activation (p17) were up-regulated. NEK7 down-regulation attenuated neurological deficits, NLRP3 inflammasomes, caspase-1 activation, and neuronal injury. The same phenomena were observed during the in vitro experiments. Furthermore, NEK7 knock-down suppressed NLRP3 inflammasome activation and pyroptosis, which were triggered by K+ efflux, and the LPS + ATP-triggered NEK7–NLRP3 complex was reversed in primary cortical neurons placed in 50 mM K+ medium. Collectively, the data demonstrated that NEK7, as a modulator, regulates NLRP3 inflammasomes and downstream neuroinflammation in response to K+ efflux, through NEK7–NLRP3 assembly, pro-caspase-1 recruitment, caspase-1 activation, and pyroptosis in nerve injuries, post-TBI. NEK7 may be a potential therapeutic target for attenuating neuroinflammation and nerve injury post-TBI.
Highlights
As one of the most common causes of mortality and disability, traumatic brain injury (TBI) causes a huge psychological and economic burden to patients, families, and societies worldwide (Barlow et al, 2018)
Levels of the proteins NIMA-related kinase 7 (NEK7), NLRP3, and caspase-1 p20 were distinctly increased at 24 h; these high levels continued until 168 h post-TBI and following gradually decreased with time, and apoptosisassociated speck-like protein containing CARD (ASC) and pro-caspase-1 levels appeared to increase slightly after TBI (Figure 1B)
IL-1β and IL-18 were immediately triggered at 2 h, TNF-α increased significantly by 4 h, and they all mildly decreased with time but still remained at high levels during 168 h post-TBI
Summary
As one of the most common causes of mortality and disability, traumatic brain injury (TBI) causes a huge psychological and economic burden to patients, families, and societies worldwide (Barlow et al, 2018). A series of complex pathophysiological processes lead to severe secondary brain injury within hours or days following acute brain injury (Maas et al, 2017). Pyroptosis can be activated by NLRs or AIM2-like receptors through the triggering of inflammasomes, which contain apoptosisassociated speck-like protein containing CARD (ASC) and caspase-1, inducing a series of inflammatory reactions post-TBI (Ge et al, 2018; Guo et al, 2018). The subcutaneous injection of IL-1 receptor antagonists has been proven in clinical practice to ameliorate IL-1-mediated brain injury following TBI by regulating the neuroinflammatory reaction (Helmy et al, 2014, 2016). Neuroinflammation, neurologic dysfunction, and nerve injury following TBI can be significantly improved by regulating the caspase-1-mediated pyroptosis signal pathway in neurons (Liu et al, 2018)
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