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Published on: February 21, 2025
Inhibition of cGAS Reduces Brain Injury and Facilitates Neurological Recovery via the STING-Mediated Signaling
Yiheng Wang1, Xuhui Yin1, Xiaoli Zhang1
1Institute of Neuroscience and Third Affiliated Hospital, Zhengzhou University, 450052 Zhengzhou, Henan, China.
Background:
Germinal matrix hemorrhage (GMH) is a common complication of premature infants with lifelong neurological consequences. Inflammation-mediated blood-brain barrier (BBB) disruption has been implicated as a main mechanism of secondary brain injury after GMH. The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in inflammation, yet its involvement in GMH pathophysiology remains unclear.
Methods:
Collagenase was injected into the right germinal matrix of postnatal day 5 (P5) mouse pups to induce GMH. Either RU.521, or RU.521 combined with a STING agonist SR-717 was administered to the mice after GMH. The number of microglia, proinflammatory cytokines, microglial polarization, BBB permeability, demyelination, and axon degeneration were analyzed by immunofluorescence staining, western blotting, and quantitative real-time PCR. Neurobehavioral functions were evaluated using novel object recognition, Y-maze, and rotarod tests.
Results:
After induction of GMH, cGAS and STING were upregulated in the peri-hematomal area with a peak at 24 h, and they were mainly expressed in microglia. RU.521 treatment decreased the number of microglia, proinflammatory cytokines and microglial polarization, preserved BBB integrity, and decreased its permeability after GMH. Moreover, RU.521 decreased GMH-mediated upregulation of STING, phosphorylated TANK-binding kinase 1 (phospho-TBK1), phosphorylated interferon regulatory factor 3 (phospho-IRF3), and interferon-β (IFN-β), diminished demyelination, axon degeneration, and neurological deficits. The STING agonist SR-717 blunted RU.521-induced downregulation of phospho-TBK1, phospho-IRF3 and IFN-β and blocked RU.521-mediated inhibition of inflammation, protected against BBB breakdown, white matter lesions, and neurological dysfunction after GMH.
Conclusions:
Inhibition of cGAS improved white matter lesions and neurological dysfunction by modulating the microglial polarization towards decreased neuroinflammation and maintaining BBB integrity through STING-mediated type I IFN-β production. Thus, cGAS may be a potential therapeutic target for the treatment of GMH.
Insights
Inhibiting the cGAS-STING pathway reduces inflammation and brain damage after germinal matrix hemorrhage (GMH) in premature infants. This suggests cGAS is a potential therapeutic target for treating GMH and its neurological consequences.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Germinal matrix hemorrhage (GMH) is a frequent complication in premature infants, leading to long-term neurological deficits.
- Inflammation-driven disruption of the blood-brain barrier (BBB) is a key factor in secondary brain injury following GMH.
- The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway's role in GMH pathophysiology is not well understood.
Purpose of the Study:
- To investigate the involvement of the cGAS-STING pathway in GMH.
- To evaluate the therapeutic potential of cGAS inhibition in a mouse model of GMH.
Main Methods:
- GMH was induced in P5 mouse pups using collagenase injection.
- Mice received RU.521 (a cGAS inhibitor) or RU.521 plus a STING agonist (SR-717).
- Analysis included microglial activation, cytokine levels, BBB permeability, demyelination, axon degeneration, and neurobehavioral tests.
Main Results:
- GMH upregulated cGAS and STING, primarily in microglia.
- RU.521 treatment reduced microglial activation, inflammation, BBB permeability, demyelination, and neurological deficits.
- The STING agonist SR-717 counteracted the protective effects of RU.521, indicating STING's critical role.
Conclusions:
- Inhibition of cGAS ameliorates white matter damage and neurological dysfunction in GMH.
- This occurs by shifting microglial polarization to reduce neuroinflammation and maintaining BBB integrity via STING-dependent type I interferon-beta production.
- cGAS represents a promising therapeutic target for GMH treatment.
