STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia

Morozzi, Giulio; Rothen, Julian; Toussaint, Gauthier; Lange, Katrina De; Westritschnig, Katrin; Doelemeyer, Arno; Ueberschlag, Vanessa Pitiot; Kahle, Peter; Lambert, Christian; Obrecht, Michael; Beckmann, Nicolau; Ritter, Veronique; Panesar, Moh; Stauffer, Daniela; Garnier, Isabelle; Müeller, Matthias; Guerini, Danilo; Keller, Caroline Gubser; Knehr, Judith; Roma, Guglielmo; Bidinosti, Michael; Brachat, Sophie; Morvan, Frédéric; Fornaro, Mara

doi:10.1016/j.isci.2021.103434

Cited by 7 publications

(5 citation statements)

References 65 publications

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“…The gene Nlrp3 is a key player in inflammasome formation, which contributes to neuroinflammation and cell death [66,67]. The genes Mb21d1 and Tmem173 encode two key proteins in the cGAS/STING pathway of the innate immune response, which has been shown to be activated in the microglia of the spinal cord after sciatic nerve injury [68]. Furthermore, several genes (Apoe, Blnk, and autophagy-related genes Lamp1, Pink1) were found to be downregulated in SCI/Becn1 +/mice compared to SCI/WT animals.…”

Section: Discussionmentioning

confidence: 99%

Impairment of autophagy after spinal cord injury potentiates neuroinflammation and motor function deficit in mice

Li¹,

Lei²,

Ritzel³

et al. 2022

Theranostics

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Autophagy is a catabolic process that degrades cytoplasmic constituents and organelles in the lysosome, thus serving an important role in cellular homeostasis and protection against insults. We previously reported that defects in autophagy contribute to neuronal cell damage in traumatic spinal cord injury (SCI). Recent data from other inflammatory models implicate autophagy in regulation of immune and inflammatory responses, with low levels of autophagic flux associated with pro-inflammatory phenotypes.In the present study, we examined the effects of genetically or pharmacologically manipulating autophagy on posttraumatic neuroinflammation and motor function after SCI in mice. Methods: Young adult male C57BL/6, CX3CR1-GFP, autophagy hypomorph Becn1 +/-mice, and their wildtype (WT) littermates were subjected to moderate thoracic spinal cord contusion. Neuroinflammation and autophagic flux in the injured spinal cord were assessed using flow cytometry, immunohistochemistry, and NanoString gene expression analysis. Motor function was evaluated with the Basso Mouse Scale and horizontal ladder test. Lesion volume and spared white matter were evaluated by unbiased stereology. To stimulate autophagy, disaccharide trehalose, or sucrose control, was administered in the drinking water immediately after injury and for up to 6 weeks after SCI. Results: Flow cytometry demonstrated dysregulation of autophagic function in both microglia and infiltrating myeloid cells from the injured spinal cord at 3 days post-injury. Transgenic CX3CR1-GFP mice revealed increased autophagosome formation and inhibition of autophagic flux specifically in activated microglia/macrophages. NanoString analysis using the neuroinflammation panel demonstrated increased expression of proinflammatory genes and decreased expression of genes related to neuroprotection in Becn1 +/-mice as compared to WT controls at 3 days post-SCI. These findings were further validated by qPCR, wherein we observed significantly higher expression of proinflammatory cytokines. Western blot analysis confirmed higher protein expression of the microglia/macrophage marker IBA-1, inflammasome marker, NLRP3, and innate immune response markers cGAS and STING in Becn1 +/-mice at 3 day after SCI. Flow cytometry demonstrated that autophagy deficit did not affect either microglial or myeloid counts at 3 days post-injury, instead resulting in increased microglial production of proinflammatory cytokines. Finally, locomotor function showed significantly worse impairments in Becn1 +/-mice up to 6 weeks after SCI, which was accompanied by worsening tissue damage. Conversely, treatment with a naturally occurring autophagy inducer trehalose, reduced protein levels of p62, an adaptor protein targeting cargo to autophagosomes as well as the NLRP3, STING, and IBA-1 at 3 days post-injury. Six weeks of trehalose treatment after SCI led to improved motor function recovery as compared to control group, which was accompanied by reduced tissue damage.

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Section: Discussionmentioning

confidence: 99%

Impairment of autophagy after spinal cord injury potentiates neuroinflammation and motor function deficit in mice

Li¹,

Lei²,

Ritzel³

et al. 2022

Theranostics

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“…This inflammatory response is characterized by secretion of IL-10 and TGF-, polarization of macrophages to an M2 subtype, and infiltration of Tregs 44,46,[74][75][76][77] all are known suppressors of anti-tumoral immunity. The degraded myelin fragments are known damage-associated molecular patterns (DAMPs) molecules, capable of stimulating an IFN-I response by cells in the peri-neural niche 78 . In parallel to the continuous damage inflicted by cancer cells, the IFN-I signaling by itself can propagate the nerve degeneration process [79][80][81] and promote the cycle.…”

Section: Discussionmentioning

confidence: 99%

Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by IL-6 blockade

Amit

Baruch

Nagarajan

et al. 2023

Preprint

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While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) – known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.

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“…Furthermore, activating IFN-I/IFNAR signaling suppressed sodium channel and calcium channel activity (95). However, it has been observed that STING1 can be expressed in macrophages, microglia, and the spinal cord after PNI and spinal cord injury (96,97), raising the possibility that the effects of STING1 may go beyond its actions with DRG sensory neurons.…”

Section: Primary Sensory Neurons: Driving Stimulus-evoked Painmentioning

confidence: 99%

Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem

Ghazisaeidi

Muley

Salter

2023

Annu. Rev. Pharmacol. Toxicol.

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The study of chronic pain continues to generate ever-increasing numbers of publications, but safe and efficacious treatments for chronic pain remain elusive. Recognition of sex-specific mechanisms underlying chronic pain has resulted in a surge of studies that include both sexes. A predominant focus has been on identifying sex differences, yet many newly identified cellular mechanisms and alterations in gene expression are conserved between the sexes. Here we review sex differences and similarities in cellular and molecular signals that drive the generation and resolution of neuropathic pain. The mix of differences and similarities reflects degeneracy in peripheral and central signaling processes by which neurons, immune cells, and glia codependently drive pain hypersensitivity. Recent findings identifying critical signaling nodes foreshadow the development of rationally designed, broadly applicable analgesic strategies. However, the paucity of effective, safe pain treatments compels targeted therapies as well to increase therapeutic options that help reduce the global burden of suffering.

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STING regulates peripheral nerve regeneration and colony stimulating factor 1 receptor (CSF1R) processing in microglia

Cited by 7 publications

References 65 publications

Impairment of autophagy after spinal cord injury potentiates neuroinflammation and motor function deficit in mice

Impairment of autophagy after spinal cord injury potentiates neuroinflammation and motor function deficit in mice

Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by IL-6 blockade

Neuropathic Pain: Mechanisms, Sex Differences, and Potential Therapies for a Global Problem

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