STING mediates neuroinflammatory response by activating NLRP3‐related pyroptosis in severe traumatic brain injury

Abstract

Long‐term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced by inflammatory response is involved in the neurological deficits post‐TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)–nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight‐drop plus blood loss reinfusion model. Selective STING agonist ADU‐S100 or antagonist C‐176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase‐1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C‐176 alleviated TBI‐induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU‐S100 exacerbated TBI‐induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis‐associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase‐1 and GSDMD N‐terminal expression. In contrast, the administration of C‐176 showed anti‐pyroptotic effects. The neuroprotective effects of C‐176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post‐TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING–NLRP3 signaling is a potential therapeutic target in TBI‐induced neurological dysfunction.

Neutrophil extracellular traps exacerbate microglia/macrophages-mediated neuroinflammation via cGAS in mice with traumatic brain injury

“…Previous studies have demonstrated that the cGAS-STING pathway is a major cytosolic DNA sensor and plays a vital role in the microglial activity and neuroin ammatory responses after TBI [29,43,44]. Consistently, our results showed that TBI led to the upregulation of STING, activation of TBK1 and IRF3, and induction of STING-associated IFN-β and IL-6.…”

“…The STING antagonist C-176 (S6575, Selleck, USA) was dissolved in a stock solution containing 5% dimethyl sulfoxide (DMSO) and 95% corn oil and then diluted in saline (5% v/v). As reported previously [29], 10 mg/kg C-176 or vehicle (saline containing 5% stock solution) was administered i.p. 1 h after TBI and then every day until the mice were killed.…”

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

“…The STING antagonist C-176 (S6575, Selleck, USA) was dissolved in a stock solution containing 5% dimethyl sulfoxide (DMSO) and 95% corn oil and then diluted in saline (5% v/v). As previously reported ( 29 ), 10 mg/kg C-176 or an equal volume of vehicle (saline containing 5% stock solution) was administered i.p. 1 h after TBI and once per day for three consecutive days.…”

“…Recently studies have revealed that STING not only provokes the TBK1/IRF3/IFNs pathway in a classical way but also is involved in the activation of ER stress and unfolded protein response (UPR) ( 25 – 27 ). STING has been reported to play an important role in regulating the neuroinflammatory process and pyroptosis after TBI ( 28 , 29 ), but its effects on NLRP1 inflammasome-mediated neuronal cell death have not been explored in TBI. Interestingly, Inositol-requiring enzyme-1 alpha (IRE1α), one of the sensor proteins in the endoplasmic reticulum associated with ER stress, has been shown to regulate NLRP1-mediated neuronal pyroptosis in a neonatal hypoxic-ischemic encephalopathy rat model ( 30 ).…”

Pharmacological inhibition of STING signaling attenuates MPTP-induced neuroinflammation and neurodegeneration in mouse parkinsonian models

“…Many neuroin ammatory diseases, such as ischemic injury, subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), Alzheimer's disease (AD), and PD are characterized by overactivation of the cGAS-STING pathway and expression of type I interferon (IFN) and in ammatory cytokines which underscore pathological progression [6][7][8][9][10][11]. Thus, STING has been recognized as a critical and promising therapeutic target for various neuroin ammatory diseases.…”