Stem Cell-Derived Exosomes Ameliorate Doxorubicin-Induced Muscle Toxicity through Counteracting Pyroptosis

Abstract

Doxorubicin (Dox)-induced muscle toxicity (DIMT) is a common occurrence in cancer patients; however, the cause of its development and progression is not established. We tested whether inflammation-triggered cell death, “pyroptosis” plays a role in DIMT. We also examined the potential role of exosomes derived from embryonic stem cells (ES-Exos) in attenuating DIMT. C57BL/6J mice (10 ± 2 wks age) underwent the following treatments: Control (saline), Dox, Dox+ES-Exos, and Dox+MEF-Exos (mouse-embryonic fibroblast-derived exosomes, negative control). Our results demonstrated that Dox significantly reduced muscle function in mice, which was associated with a significant increase in NLRP3 inflammasome and initiation marker TLR4 as compared with controls. Pyroptosis activator, ASC, was significantly increased compared to controls with an upregulation of specific markers (caspase-1, IL-1β, and IL-18). Treatment with ES-Exos but not MEF-Exos showed a significant reduction in inflammasome and pyroptosis along with improved muscle function. Additionally, we detected a significant increase in pro-inflammatory cytokines (TNF-α and IL-6) and inflammatory M1 macrophages in Dox-treated animals. Treatment with ES-Exos decreased M1 macrophages and upregulated anti-inflammatory M2 macrophages. Furthermore, ES-Exos showed a significant reduction in muscular atrophy and fibrosis. In conclusion, these results suggest that DIMT is mediated through inflammation and pyroptosis, which is attenuated following treatment with ES-Exos.

BMP-7 Attenuates Inflammation-Induced Pyroptosis and Improves Cardiac Repair in Diabetic Cardiomyopathy

“…However, whether the presence of inflammation involves the recently recognized pyroptotic cell death in the diabetic heart [5,6] has gained attraction, but detailed understanding on inflammatory cells and the pyroptotic pathway remains unknown. The initiation of pyroptosis is characterized by an inflammasome complex formation, caspase-1 and IL-1β found in various diseases [7,8]. The prevalence of the pyroptotic pathway as well as addition signaling molecules in diabetic cardiomyopathy is complex and understudied.…”

“…Recent heart studies suggest that there is a presence of sterile inflammation involving the upregulation of endogenous inducers called damage-associated molecular patterns (DAMPs) [8,9]. These upregulated DAMPs can be initiated by apoptosis, necrosis, or other cellular processes that occur when organs are challenged by an injury [10].…”

“…These upregulated DAMPs can be initiated by apoptosis, necrosis, or other cellular processes that occur when organs are challenged by an injury [10]. Subsequent to DAMPs initiation, inducers directly bind to toll-like receptor-4 (TLR4)-nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain containing 3 (NLRP3) complex and initiate the pyroptotic cascade [8,9,11]. Recently, NIMA-related kinase 7 (Nek7) was found to have a role in oligomerization and activation of NLRP3 inflammasome complex [12,13].…”

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

“…Importantly, Gilliam et al highlighted that these symptoms are dependent on the activity of pro-inflammatory cytokine, TNF-α [ 50 ]. This pro-inflammatory scenario has been shown to promote pyroptosis, a biological process of programmed cell death, which is characterised by the nucleotide binding oligmerisation domain (NOD), leucine rich repeat-containing proteins (NLR) family member, NRLP3 inflammasome formation, and activation of apoptotic caspases [ 51 , 52 ]. Furthermore, TNF-α mediates skeletal muscle contractile dysfunction through enhanced ROS production [ 53 ], although this is considered to be an additive effect to DOX-induced oxidative stress.…”

Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells

“…In tumor environment, macrophages are often associated with tumor cells to regulate tumorigenesis and metastasis of cancers ( Li et al, 2020b ; Wang and Ilyas, 2020 ). In addition, the macrophages of the tumor environment showing oncogenic effects are considered as tumor-associated macrophages (TAMs), which usually exhibit M2 phenotype ( Dessouki et al, 2020 ). The correlation between tumor cells and TAMs has been revealed some cancers (gastric cancer, pancreatic cancer, et al) ( Gao et al, 2020 ; Zhou et al, 2021 ).…”