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J Neuroinflammation Review—Wenfei Ni/Kailiang Zhou focused on the important role of STING pathway in neuroinflammation and cell death after CNS injury

 Last Update: 2022-10-20
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Written by Hu Xinli - Wang Sizhen, Fang Yiyi

Editor—Summer Leaf

Central Nervous System (CNS) injury refers to the damage of the brain and spinal cord to external factors, mainly including traumatic brain injury (TBI), spinal cord injury ().
SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE), among others [1–4].

Due to the poor repair and regeneration ability of nerve cells, serious sequelae are often caused after injury, which brings a heavy burden to the patient's family and society [5].

However, the current treatment of CNS injury has not achieved satisfactory results, so it is of great practical significance to find effective therapeutic targets and treatment options.

The innate immune response plays an important role in CNS injury by repairing damaged tissues as well as the host to fight off infection and coordinating the healing of injured tissues [6].

CNS injury usually occurs at the moment of injury, but the inflammatory microenvironment and uncontrolled cell death after secondary injury can further exacerbate the injury [7].

Therefore, controlling neuroinflammation and inhibiting cell death are essential
for the physiological function of the CNS as well as post-injury repair.

Interferon gene stimulatory factor (Stimulator of Interferon Genes, STING As a central immune molecule in many signaling pathways, it is usually in a self-inhibited state in the form of dimers, and protein configuration changes occur after stimulation by upstream signals, and then are activated, which in turn causes the activation and production of a series of downstream immune cells and inflammatory factors, thereby promoting the occurrence of inflammatory reactions in the body and producing corresponding clinical symptoms [8].

Studies have shown that the STING pathway is involved in the inflammatory response and nerve cell death after
CNS injury.
Therefore, the modulated cGAS-STING signaling pathway has become a frontier hot spot
in the research of CNS therapy and post-injury regenerative repair.

On October 4, 2022, the team of Ni Wenfei and Zhou Kailiang from the Second Affiliated Hospital of Wenzhou Medical University/Zhejiang Key Laboratory of Orthopedics held a meeting in the Journal of Neuroinflammation Published a review "Emerging role of STING signalling in CNS injury: infammation, autophagy, necroptosis, ferroptosis and pyroptosis", first author Dr.
Xinli Hu and Haojie Zhang, M.
S.
, Corresponding Author Wenfei Ni ( Wenfei Ni) chief physician and associate researcher
of Kailiang Zhou.
This article systematically summarizes the frontier progress of STING abnormal activation to promote inflammation and cell death in CNS injury research, in addition STING signaling is involved in programmed cell death during CNS injury [Autophagy, cell pyrosis Pyroptosis), Ferroptosis, and Necroptosis].
of the latest developments
.
On this basis, the potential drug regulation cGAS-STING signaling pathway in CNS damage is summarized It provides new ideas
for the treatment of CNS injury.

First, the cGAS-STING signal path

cGAS (circular GMP-AMP synthetase) recognizes double-stranded DNA in the cytoplasm and catalyzes the synthesis of GTP and ATP into loops GMP-AMP（cGAMP）[9]
。 cGAMP binds to and activates the endoplasmic reticulum protein STING, prompting STING translocation to the Golgi apparatus, which can subsequently activate the downstream TBK1, as well as the phosphorylated transcription factor IRF3, cytosolic IRF3 dimer enters the nucleus after phosphorylation, resulting in induction and I of IRF3 target gene transcription The release of type interferon, which promotes the occurrence of inflammation [10] (Figure 1).

Figure 1 cGAS-STING signaling path

(Source: Hu XL et al, J Neuroinflammation, 2022).

Second, cGAS-STING signaling pathway and CNS damage

In CNS including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE).
In the injury disease, excessive activation of the cGAS-STING signaling pathway has been found to mediate the overexpression of inflammation and the programmed death
of nerve cells.
Overactivated inflammation and cell death that cannot be effectively suppressed are considered to be one of the core problems in CNS injury, and how to inhibit excessive inflammatory activation and programmed cell death is the core step of
treatment.
This review summarizes the activation of STING in different types of CNS injuries and focuses on the latest research progress
.

cGAS-STING signaling pathway and programmed cell death

(I) cGAS-STING The autophagy process with autophagy consists of five stages: induction phase - nucleation - extension - autophagosome formation - lysis [11]
。 cGAS-STING activation can initiate autophagy, after the start of autophagy, cGAS-STING ubiquitinated and bound to p62, and then packaged into an autophagosome, and combined with lysosomes to form autophagy lysosomes, digest autophagy substrates, The final process of autophagy is completed (Figure 2).

Figure 2 cGAS-STING and autophagy (Source: Hu XL et al, J Neuroinflammation, 2022 ）

(ii) cGAS-STING and cell necropolis apoptosis

Activation of the cGAS-STING signaling pathway can mediate cell necrotizing apoptosis [12].

Intracytoplasmic DNA activates the cGAS-STING signaling pathway leading to the production
of IFN and TNF.
The binding of TNF to TNFR1 results in the activation of RIPK1/RIPK3 when Caspase-8 is inhibited
.
RIPK1/RIPK3 can phosphorylate MLKL leading to cell necrotic apoptosis
.
In addition, the overexpression of IFN can upregulate RIPK3 and MLKL (Figure 3).

。 Figure 3 cGAS-STING and cell necroposis (Source: Hu XL et al, J Neuroinflammation , 2022）

(iii) cGAS-STING and cell iron death

System Xc− is a reversing carrier of isodimeric cystine/glutamate that introduces cystine to maintain redox homeostasis, which is then reduced to cysteine and used to synthesize the main antioxidant, GSH [13].

The core regulatory molecule of cell iron death is GPX4, a family of enzymes that reduces peroxides
at the expense of the oxidation of two GSH molecules.
Inactivation of GPX4 can lead to iron death in cells [14].

In addition, GPX4 can promote STING carbonylation and inhibit its transfer from the endoplasmic reticulum to the Golgi complex, which plays a role in inhibiting the expression
of the cGAS-STING signaling pathway.
Therefore, GPX4 is the junction of cell siderogenesis and STING (Figure 4).

。

Figure 4 cGAS-STING and cell iron death

(Source: Hu XL et al, J Neuroinflammation, 2022).

(iv) cGAS-STING and cytopyrotic melanoma deficiency factor 2 (Absent in Melanoma 2, AIM2 Inflammasomes are a class of inflammasomes primarily expressed in neurons, and are the only known inflammasomes that recognize ectopic double-stranded DNA.

Activated AIM2 inflammasomes can induce pyrosis in neurons [15].

At the same time, cGAS-STING-mediated increase in IFN can promote AIM2 activity, thereby increasing the expression of Caspase-1 and promoting cell pyrosis
。 In addition, Caspase-1 overexpression and potassium efflux due to pyroptosis can inhibit cGAS function (Figure 5).

Figure 5 cGAS-STING and cell pyrosis

(Source: Hu XL et al, J Neuroinflammation, 2022).

Potential strategies for inhibiting STING signaling pathway in the treatment of CNS injury

Aseptic inflammation and cell death caused by the cGAS-STING signaling pathway play an important role
in CNS injury.
Inhibitors of the cGAS-STING pathway may be potential targets for CNS injury therapy
.
cGAS, which catalyzes the production
of cGAMP by recognizing DNA in the cytoplasm after cell death.
The cGAMP then transmits a signal to the downstream STING, which translocates to the Golgi apparatus to activate downstream TBK1 and phosphorylated transcription factors IRF3, the cytosolic IRF3 dimer, enters the nucleus after phosphorylation, resulting in induction of transcription of the IRF3 target gene and release of type I interferon
.
This process activates an innate immune response [16].

Therefore, DNA in the cytoplasm is an important factor in the activation of cGAS-STING, so it can reduce DNA in the cytoplasm and inhibit cGAS and STING to suppress the cGAS-STING signaling
pathway.
A number of drugs have been shown to inhibit the cGAS–STING signaling pathway and provide viable treatments for related diseases (Table 1) [17-20].

。 However, more research
is needed on the therapeutic effect of inhibiting the cGAS-STING pathway in the field of CNS injury.

Table 1 Inhibitors of the cGAS-STING signaling pathway

(Source: Hu XL et al, J Neuroinflammation, 2022).

V.
Summary and prospects

Excessive inflammatory response and uncontrolled nerve cell death play an important role
in CNS injury.
As a newly discovered pathway in recent years, STING signaling pathway plays a very important role
in regulating neuroinflammation and cell death.
At present, there is an increasing number of research literature on cGAS-STING signaling pathway on CNS injury, and it is urgent to comprehensively summarize the role of cGAS-STING signaling pathway on CNS injury.
Lay a solid foundation
for follow-up research.
Therefore, the purpose of this review is to summarize the research progress of cGAS-STING signaling pathway in CNS injury.
The link between the cGAS-STING signaling pathway and programmed cell death was explored.
Finally, the possible methods and strategies for alleviating neuroinflammation and cell death using cGAS-STING signaling pathway as a target are summarized, aiming to provide new ideas
for CNS injury.

Original link: style="margin-bottom: 0px;white-space: normal;margin-top: 0px;">

National Natural Science Foundation of China (8207219), Zhejiang Public Welfare Technology Project (LGF20H150003), Natural Science Foundation of Zhejiang Province (LY17H060009, Y21H060050), Wenzhou Science and Technology Bureau Fund Support Project (Y20210438
。

First authors: Dr.
Hu Xinli (first from left), Master Zhang Haojie (second from left); Corresponding authors: Associate Researcher Zhou Kailiang (second from right), Chief Physician Ni Wenfei (first from right).

(Photo courtesy of: Zhou Kailiang/Ni Wenfei team)

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