Pharmacological Inhibition of STING/TBK1 Signaling Attenuates Myeloid Fibroblast Activation and Macrophage to Myofibroblast Transition in Renal Fibrosis

Zeng, Haimei; Gao, Ying; Yu, Wenqiang; Liu, Jiping; Zhong, Chaoqun; Su, Xi; Wen, Sijian; Liu, Hua

doi:10.3389/fphar.2022.940716

Cited by 12 publications

(4 citation statements)

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“…Furthermore, the role of the STING pathway in liver, kidney and lung fibrosis has also been demonstrated [143][144][145]. Conversely, drug inhibition of STING/TBK1 signaling has been shown to reduce the conversion of bone marrow fibroblasts and macrophages into myofibroblasts [146], thus presenting is a promising pathway for targeted fibrosis therapy. Ferroptosis is a type of cell death that is dependent on iron and causes oxidative DNA damage.…”

Section: Cgas/sting Pathway-identifier Of Dna Damagementioning

confidence: 99%

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances

Yu,

Xu,

Song

et al. 2023

J Transl Med

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Cancer remains the leading cause of death around the world. In cancer treatment, over 50% of cancer patients receive radiotherapy alone or in multimodal combinations with other therapies. One of the adverse consequences after radiation exposure is the occurrence of radiation-induced tissue fibrosis (RIF), which is characterized by the abnormal activation of myofibroblasts and the excessive accumulation of extracellular matrix. This phenotype can manifest in multiple organs, such as lung, skin, liver and kidney. In-depth studies on the mechanisms of radiation-induced fibrosis have shown that a variety of extracellular signals such as immune cells and abnormal release of cytokines, and intracellular signals such as cGAS/STING, oxidative stress response, metabolic reprogramming and proteasome pathway activation are involved in the activation of myofibroblasts. Tissue fibrosis is extremely harmful to patients' health and requires early diagnosis. In addition to traditional serum markers, histologic and imaging tests, the diagnostic potential of nuclear medicine techniques is emerging. Anti-inflammatory and antioxidant therapies are the traditional treatments for radiation-induced fibrosis. Recently, some promising therapeutic strategies have emerged, such as stem cell therapy and targeted therapies. However, incomplete knowledge of the mechanisms hinders the treatment of this disease. Here, we also highlight the potential mechanistic, diagnostic and therapeutic directions of radiation-induced fibrosis.

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Section: Cgas/sting Pathway-identifier Of Dna Damagementioning

confidence: 99%

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances

Yu,

Xu,

Song

et al. 2023

J Transl Med

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“…RU.521 has been used to improve disease outcomes in rodent models of neuroinflammation caused by subarachnoid hemorrhage and cerebral venous sinus thrombosis, colitis, sepsis-induced organ injury, , acetaminophen-induced liver injury, acute lung injury, hypertensive heart injury, ischemic injury in the lung and neonatal brain, femoral fracture healing, and aging-related endothelial dysfunction . Additionally, administration of H-151 has improved outcomes in rodent models of acute kidney injury (AKI), renal fibrosis, amyotrophic lateral sclerosis (ALS), sepsis-induced organ injury, , psoriasis, ischemia-reperfusion injury in the intestine, myocardial infarction, LPS-induced acute lung injury, , Alzheimer’s, and neuropathic pain resulting from chronic constriction injury . However, early experiences with these molecules has also identified several potential pharmacological barriers that may inhibit the translation of RU.521 and H-151 (and potentially cGAS/STING inhibitors more generally).…”

Section: Introductionmentioning

confidence: 99%

STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases

Pastora,

Namburu,

Arora

et al. 2024

ACS Appl. Bio Mater.

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Aberrant activation of the cyclic GMP-AMP synthase (cGAS)/ Stimulator of Interferon Genes (STING) pathway has been implicated in the development and progression of a myriad of inflammatory diseases including colitis, nonalcoholic steatohepatitis, amyotrophic lateral sclerosis (ALS), and age-related macular degeneration. Thus, STING pathway inhibitors could have therapeutic application in many of these inflammatory conditions. The cGAS inhibitor RU.521 and the STING inhibitor H-151 have shown promise as therapeutics in mouse models of colitis, ALS, and more. However, these agents require frequent high-dose intraperitoneal injections, which may limit translatability. Furthermore, long-term use of systemically administered cGAS/STING inhibitors may leave patients vulnerable to viral infections and cancer. Thus, localized or targeted inhibition of the cGAS/STING pathway may be an attractive, broadly applicable treatment for a variety of STING pathway-driven ailments. Here we describe STING-Pathway Inhibiting Nanoparticles (SPINS)−poly(lacticco-glycolic acid) (PLGA) nanoparticles loaded with RU.521 and H-151−as a platform for enhanced and sustained inhibition of cGAS/STING signaling. We demonstrate that SPINs are equally or more effective at inhibiting type-I interferon responses induced by cytosolic DNA than free H-151 or RU.521. Additionally, we describe a SPIN formulation in which PLGA is coemulsified with poly(benzoyloxypropyl methacrylamide) (P(HPMA-Bz)), which significantly improves drug loading and allows for tunable release of H-151 over a period of days to over a week by varying P(HPMA-Bz) content. Finally, we find that all SPIN formulations were as potent or more potent in inhibiting cGAS/STING signaling in primary murine macrophages, resulting in decreased expression of inflammatory M1-like macrophage markers. Therefore, our study provides an in vitro proof-of-concept for nanoparticle delivery of STING pathway inhibitors and positions SPINs as a potential platform for slowing or reversing the onset or progression of cGAS/ STING-driven inflammatory conditions.

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“…Currently, several studies have discovered that the cGAS-STING pathway not only serves a protective role in combating foreign pathogens but also plays a signi cant role in the initiation and progression of various conditions such as infections, in ammation, tumors, autoimmune diseases, and other diseases [11] . Moreover, there have been reports indicating the involvement of the STING pathway in the pathogenesis of brotic diseases, including pulmonary brosis, liver brosis, and renal brosis [12][13][14] . It has been demonstrated that STING is highly expressed on hematopoietic cells, such as macrophages [15] and the presence of macrophages is essential for the proper healing of wounds.…”

Section: Introductionmentioning

confidence: 99%

Macrophage STING signaling promotes fibrosis in benign airway stenosis via IL6-STAT3 axis

Shi,

Chen,

Yang

et al. 2024

Preprint

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Benign airway stenosis (BAS) caused by tracheal intubation resuscitation measures is a difficult complication to ignore in the management of critically ill patients. However, the pathogenesis of this disease, which is characterized histologically by tracheal fibrosis, remains poorly understood. It has been shown that post-injury inflammatory processes play a key role in tissue fibrosis. However, we remain unclear about the relationship between inflammation induced by mechanical injury and BAS after tracheal intubation. Here, we found STING expression was increased in trachea after injury and inhibition or deletion of STING can alleviate tracheal fibrosis in BAS mice. Then, we reveal that released tracheal epithelial cell DNA resulting from mechanical injury activates macrophage STING. Further, macrophages with activated cGAS-STING pathway promote fibroblast fibrosis in the trachea via the IL6-STAT3 axis. We determined that the cGAS-STING pathway in macrophages is critical in causing tracheal fibrosis and ultimately benign airway stenosis. Our results provide a key cornerstone for future treatment of benign airway stenosis caused by mechanical injury.

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Pharmacological Inhibition of STING/TBK1 Signaling Attenuates Myeloid Fibroblast Activation and Macrophage to Myofibroblast Transition in Renal Fibrosis

Cited by 12 publications

References 50 publications

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances

Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances

STING-Pathway Inhibiting Nanoparticles (SPINs) as a Platform for Treatment of Inflammatory Diseases

Macrophage STING signaling promotes fibrosis in benign airway stenosis via IL6-STAT3 axis

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