Abstract
Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto-siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.
Keywords:
FTO; N6-methyladenosine; entacapone; inflammasome; sepsis.
Copyright © 2021 Luo, Wang, Sun, Yue, Zhou, Yang, Rong, Yang, Xiong, Yu, Zhang, Wang and Li.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO / antagonists & inhibitors
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics*
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
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Animals
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Disease Models, Animal
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Gene Expression
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Gene Silencing
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Humans
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Inflammasomes / metabolism*
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Interleukin-1beta / biosynthesis
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Lipopolysaccharides / adverse effects
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Liposomes
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Macrophage Activation / genetics
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Macrophage Activation / immunology
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Models, Biological
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NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
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RNA Interference
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Shock, Septic / drug therapy
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Shock, Septic / etiology*
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Shock, Septic / metabolism*
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Shock, Septic / pathology
Substances
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Inflammasomes
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Interleukin-1beta
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Lipopolysaccharides
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Liposomes
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NLR Family, Pyrin Domain-Containing 3 Protein
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RNA, Small Interfering
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FTO protein, mouse
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Alpha-Ketoglutarate-Dependent Dioxygenase FTO
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FTO protein, human