NEK7 Regulates NLRP3 Inflammasome Activation and Neuroinflammation Post-traumatic Brain Injury

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.

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

“…There has been increasing attention on the molecular mechanisms of NLRP3 in a number of diseases. Recent studies have reported significant protective effects resulting from suppression of NLRP3 inflammasome activation in liver fibrosis, systemic sclerosis, systemic lupus erythematosus, systemic sclerosis, diabetes, inflammasome-related eye disease, inflammatory bowel disease, rheumatoid arthritis, and CNS diseases (Zhou et al, 2016;Alegre et al, 2017;Rovira-Llopis et al, 2018;Shen et al, 2018;Yerramothu et al, 2018;Chen et al, 2019a). Meng et al (2019) demonstrated that PPARγ activation exerts an anti-inflammatory effect by suppressing NLRP3 inflammasome activation in spinal cord-derived neurons.…”

The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

“…NEK7 has been found in NLRP3/ASC complexes: ASC complexes require NLRP3 complex formation and the interaction between NEK7 and NLRP3 is essential [ 83 ]. A recent study demonstrated the important role of NEK7 in regulating NLRP3 inflammasome, in fact, NEK7 knockdown significantly decreased caspase-1 activation, thus inhibiting pyroptosis and downstream inflammation following TBI [ 84 ]. However, the whole mechanism that explains how NEK7 modulates NLPRP3 inflammasome in neurons is still unknown.…”

Slc6a3-dependent expression of a CAPS-associated Nlrp3 allele results in progressive behavioral abnormalities and neuroinflammation in aging mice

“…Subsequent studies indicate significant NLRP3 expression and inflammasome activity in intestinal epithelial cells that influence inflammatory bowel disease progression [25,26]. Sustained NLRP3 expression was observed in distressed neurons surrounding ischemic stroke [27] as well as in primary cortical neurons in an experimental traumatic brain injury (TBI) model [28]. Expression of the inflammasome family pattern recognition receptors NLRP1 and AIM2 has also been reported in neurons in mouse and rat models respectively [29,30].…”