10-Gingerol attenuates alcohol-induced colon injury by modulating IL-36R and downstream cGAS-STING signaling to suppress macrophage inflammation and ferroptosis.
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引用次数: 0
Abstract
Ethnopharmacological relevance: Ginger (Zingiber officinale Roscoe, Zingiberaceae) is traditionally used in Chinese and Ayurvedic/Tibb-Unani medicine for gastrointestinal and inflammatory disorders. Its bioactive constituent 10-gingerol (10-G) exhibits intestinal anti-inflammatory activity, providing a rationale for investigating its protective effects against alcohol-induced colon injury.
Aim of the study: To investigate whether 10-G attenuates alcohol-induced colon injury by modulating interleukin-36 receptor (IL-36R) and downstream cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby reducing macrophage inflammation and ferroptosis.
Materials and methods: An alcohol-induced mouse colon injury model and lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages (MPMs) were used. Transcriptomics, Il1rl2 knockdown, complementary target-engagement assays, and STING-agonist rescue were performed.
Results: 10-G reduced IL-36R and cGAS expression and STING signaling activation, while attenuating alcohol-induced colon injury, tight-junction disruption, inflammation, and ferroptosis-related alterations. Target-engagement assays supported IL-36R engagement by 10-G. In vivo, Il1rl2 knockdown suppressed cGAS-STING signaling and attenuated inflammation- and ferroptosis-related alterations. In LPS-stimulated MPMs, 10-G attenuated inflammatory responses and ferroptosis. Il1rl2 knockdown induced changes consistent with 10-G treatment; significant shRNA × 10-G interactions indicated that the effects of 10-G were influenced by IL-36R functional status. STING reactivation counteracted the effects of 10-G and Il1rl2 knockdown on inflammatory and ferroptosis-related readouts without restoring IL-36R levels.
Conclusions: 10-G attenuates alcohol-induced colon injury by engaging and modulating IL-36R and suppressing downstream cGAS-STING signaling, thereby reducing macrophage inflammation and ferroptosis. Genetic and pharmacological evidence supports a functional upstream role for IL-36R.
期刊介绍：
The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.
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