What role of the cGAS-STING pathway plays in chronic pain?

Abstract

Chronic pain interferes with daily functioning and is frequently accompanied by depression. Currently, traditional clinic treatments do not produce satisfactory analgesic effects and frequently result in various adverse effects. Pathogen recognition receptors (PRRs) serve as innate cellular sensors of danger signals, sense invading microorganisms, and initiate innate and adaptive immune responses. Among them, cGAS-STING alerts on the presence of both exogenous and endogenous DNA in the cytoplasm, and this pathway has been closely linked to multiple diseases, including auto-inflammation, virus infection, and cancer. An increasing numbers of evidence suggest that cGAS-STING pathway involves in the chronic pain process; however, its role remains controversial. In this narrative review, we summarize the recent findings on the involvement of the cGAS-STING pathway in chronic pain, as well as several possible mechanisms underlying its activation. As a new area of research, this review is unique in considering the cGAS-STING pathway in sensory neurons and glial cells as a part of a broader understanding of pain, including potential mechanisms of inflammation, immunity, apoptosis, and autophagy. It will provide new insight into the treatment of pain in the future.

STING Contributes to Cancer-Induced Bone Pain by Promoting M1 Polarization of Microglia in the Medial Prefrontal Cortex

“…Several limitations should not be ignored in the current study. Donnelly et al proved STING activator DMXAA may facilitate analgesia, partly by increasing CD8+ T cells in the microenvironment of bone marrow tumor [ 52 ], but recent research suggested that another STING agonist, ADU-S100, activated CD8+ T cells at a low dose, while high doses led to the death of the CD8+ T cells [ 22 , 59 ]. Furthermore, STING may affect the polarization states of microglia by regulating other pathways, including NLRP3 inflammasome activation, metabolic reprogramming, or autophagy [ 29 ].…”

“…Stimulator of interferon genes (STING) is an endogenous DNA sensor which can be activated together with upstream cGAS by dsDNA of endogenous damaged cells or exogenous pathogens, to participate in pathogen defense, inflammatory response, and tumor immunity [ 21 , 22 ]. Activating STING recruits TANK-binding kinase-1 (TBK1) and phosphorylates IRF3 to relocate to the nucleus where it induces transcription of genes encoding interferons and IFN-stimulated genes such as cytokines and chemokines.…”

cGAS–STING, an important signaling pathway in diseases and their therapy

“…cGAS and STING antagonists inhibit M1 polarization of microglia and improve mechanical abnormal pain induced by spared nerve injury (SNI) 260 . After exogenous and endogenous DNAs from pathogens and damaged cells activate the cGAS–STING signaling pathway, activation of STING promotes the expression of IFN‐I and NF‐κB, ultimately leading to chronic pain 261 . In addition, the cGAS–STING signaling pathway activated by mtDNA leakage causes chronic postoperative pain by inducing IFN‐I and A1 reactive astrocytes in the spinal cord 262 .…”

STINGing away the pain: the role of interferon-stimulated genes

“…However, sensory neurons are also able to sense danger signals after injury or during infection through the expression of PPRs ( 2 , 3 ). In this context, stimulator of interferon genes (STING), a cytosolic DNA sensor that recognizes self-DNA, viral DNA, and cyclic dinucleotides produced by bacteria, has emerged as a regulator of pain signaling ( 4 ). Pharmacological activation of STING exerts antinociceptive effects in neuropathic mice ( 5 – 7 ), while deletion of the gene that encodes STING results in the development of mechanical allodynia ( 5 ).…”