Blocking cGAS-STING pathway promotes post-stroke functional recovery in an extended treatment window via facilitating remyelination.

BACKGROUND: Ischemic stroke is a major cause of worldwide death and disability, with recombinant tissue plasminogen activator being the sole effective treatment, albeit with a limited treatment window. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is emerging as the major DNA-sensing pathway to invoke immune responses in neuroinflammatory disorders. METHODS: By performing a series of neurobehavioral assessments, electrophysiological analysis, high-throughput sequencing, and cell-based assays based on the transient middle cerebral artery occlusion (tMCAO) mouse stroke model, we examined the effects and underlying mechanisms of genetic and pharmacological inhibition of the cGAS-STING pathway on long-term post-stroke neurological functional outcomes. FINDINGS: Blocking the cGAS-STING pathway, even 3 days after tMCAO, significantly promoted functional recovery in terms of white matter structural and functional integrity as well as sensorimotor and cognitive functions. Mechanistically, the neuroprotective effects via inhibiting the cGAS-STING pathway were contributed not only by inflammation repression at the early stage of tMCAO but also by modifying the cell state of phagocytes to facilitate remyelination at the sub-acute phase. The activation of the cGAS-STING pathway significantly impeded post-stroke remyelination through restraining myelin debris uptake and degradation and hindering oligodendrocyte differentiation and maturation. CONCLUSIONS: Manipulating the cGAS-STING pathway has an extended treatment window in promoting long-term post-stroke functional recovery via facilitating remyelination in a mouse stroke model. Our results highlight the roles of the cGAS-STING pathway in aggregating stroke pathology and propose a new way for improving functional recovery after ischemic stroke. FUNDING: This work was primarily funded by the National Key R&D Program of China.

Upconversion luminescence and temperature sensing properties of Ho3+,Yb3+-codoped Bi2WO6.

Ho3+ and Yb3+-codoped Bi2WO6 upconversion luminescent materials at different concentrations were prepared via a high-temperature solid-phase method. The X-ray diffraction patterns showed that Ho3+ and Yb3+ doping basically did not affect the orthorhombic crystal system structure of the Bi2WO6 matrix material. Scanning electron microscopy images showed that 3%Ho3+,10%Yb3+:Bi2WO6 consisted of irregular bulk particles with sizes in the range of 0.5-2 µm and some powder agglomeration. SEM mapping and EDS measurements of the powder showed that the elements were relatively uniformly distributed. Under 980 nm excitation, the emission intensity of Ho3+ was the largest for the 3%Ho3+- and 10%Yb3+-doped sample. With an excitation power ranging from 45 mW to 283 mW for the 3%Ho3+,10%Yb3+:Bi2WO6 sample, the relationship between the luminescence intensity and pump power was determined; the results indicated that the Ho3+ (538 nm, 546 nm, 660 nm, 756 nm) emission peaks originated from two-photon absorption. In the temperature range of 298 K-573 K, under 980 nm laser excitation, the maximum absolute temperature sensitivity Sa was 0.029% K-1 (373 K), the maximum relative temperature sensitivity Sr was 0.034% K-1 (348 K) for the Ho3+ thermally coupled energy levels 5F4/5S2, and the minimum temperature resolution δT was 1.2857 K (298 K). Under the same conditions, the maximum Sa was 51.02% K-1 (573 K), the maximum Sr was 1.85% K-1 (523 K) for the Ho3+ nonthermally coupled energy levels 5F5/5F4, and the minimum δT is 0.2477 K (448 K). The colour coordinates showed that the luminescence of the 3%Ho3+,10%Yb3+:Bi2WO6 sample gradually shifted from the green region to the red region with increasing temperature.

STING signaling in islet macrophages impairs insulin secretion in obesity.

The innate immune regulator stimulator of interferon genes (STING) mediates self-DNA sensing and leads to the induction of type I interferons and inflammatory cytokines, which promotes the progression of various inflammatory and autoimmune diseases. Innate immune system plays a critical role in regulating obesity-induced islet dysfunction, whereas the potential effect of STING signaling is not fully understood. Here, we demonstrate that STING is mainly expressed and activated in islet macrophages upon high-fat diet (HFD) feeding. Sting-/- alleviates HFD-induced islet inflammation by inhibiting the expression of pro-inflammatory cytokines and the infiltration of macrophages. Mechanically, palmitic acid incubation promotes mitochondrial DNA leakage into the cytosol and subsequently activates STING pathway in macrophages. Additionally, STING activation in macrophages impairs glucose-stimulated insulin secretion by mediating the engulfment of ß cell insulin secretory granules. Pharmacologically inhibiting STING activation enhances insulin secretion to control hyperglycemia. Together, our results reveal a regulatory mechanism in controlling the islet inflammation and insulin secretion in diet--induced obesity and suggest that selective blocking of the STING activation may be a promising strategy for treating type 2 diabetes.

m6A-mediated modulation coupled with transcriptional regulation shapes long noncoding RNA repertoire of the cGAS-STING signaling.

The cGAS-STING signaling plays pivotal roles not only in host antiviral defense but also in various noninfectious contexts. Compared with protein-coding genes, much less was known about long noncoding RNAs involved in this pathway. Here, we performed an integrative study to elucidate the lncRNA repertoire and the mechanisms modulating lncRNA's expression following cGAS-STING signaling activation. We uncovered a reliable set of 672 lncRNAs closely linked to cGAS-STING signaling activation (cs-lncRNA), which might be associated with type-I interferon response and infection-related phenotypes. The ChIP-seq analysis demonstrated that cs-lncRNA was strongly regulated at the transcriptional level. We further found N6-methyladenosine (m6A) regulatory machinery was indispensable for establishing cs-lncRNA repertoire via modulating m6A modification on cs-lncRNA transcripts and promoting the expression of signaling transduction key components, including IFNAR1. Loss of IFNAR1 led to the dysregulation of cs-lncRNAs resembled that of loss of an essential subunit of m6A writer METTL14. We also found m6A system affected transcriptional machinery to modulate cs-lncRNAs by targeting multiple crucial transcription factors. Inhibiting an m6A modification regulated transcription factor, EZH2, markedly enhanced the expression pattern of cs-lncRNAs. Taken together, our results uncovered the composition of the cs-lncRNAs and revealed m6A-mediated modulation coupled with transcriptional regulation significantly shaped cs-lncRNA repertoire.

STING inhibitors target the cyclic dinucleotide binding pocket.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.