Details

Autor(en) / Beteiligte

• Gao, Yuan
• Wang, Tao
• Cheng, Ying
• Wu, Yumin
• Zhu, Luwen
• Gu, Zhiya
• Wu, Youzhuang
• Cai, Luwei
• Wu, Yimin
• Zhang, Yidan
• Gao, Cheng
• Li, Lili
• Li, Jing
• Li, Qianqian
• Wang, Zufeng
• Wang, Ying
• Wang, Fudi
• Luo, Chengliang
• Tao, Luyang

Titel

Melatonin ameliorates neurological deficits through MT2/IL-33/ferritin H signaling-mediated inhibition of neuroinflammation and ferroptosis after traumatic brain injury

Ist Teil von

• Free radical biology & medicine, 2023-04, Vol.199, p.97-112

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Although traumatic brain injury (TBI) is a common cause of death and disability worldwide, there is currently a lack of effective therapeutic drugs and targets. To reveal the complex pathophysiologic mechanisms of TBI, we performed transcriptome analysis of the mouse cerebral cortex and immunohistochemical analysis of human cerebral tissues. The genes Mt1, Mt2, Il33, and Fth1 were upregulated post-TBI and enriched in pathways associated with the inflammatory response, oxidative phosphorylation, and ferroptosis. As an agonist of MT1/2, melatonin (MLT) confers anti-oxidant, anti-inflammatory, and anti-ferroptosis effects after TBI. However, whether these upregulated genes and their corresponding pathways are involved in the neuroprotective effect of MLT remains unclear. In this study, interventions to inhibit MT1/2, IL-33, and ferroptosis (i.e., ferritin H (Fth)-KO) were applied post-TBI. The results showed that MLT attenuated TBI-induced cerebral edema and neurological outcomes by inhibiting inflammation and ferroptosis. Mechanistically, MLT mainly suppressed inflammatory responses and ferroptosis via the activation of MT2 and IL-33 pathways. Building on the previous finding that Fth deletion increases susceptibility to ferroptosis post-TBI, we demonstrated that Fth depletion remarkably exacerbated the post-TBI inflammatory response, and abolished the anti-inflammatory effects of MLT both in vivo and in vitro. Furthermore, the post-TBI anti-inflammatory effect of MLT, which occurs by promoting the polarization of CD206+ macrophages, was dependent on Fth. Taken together, these results clarified that MLT alleviates inflammation- and ferroptosis-mediated brain edema and neurological deficits by activating the MT2/IL-33/Fth pathway, which provides a novel target and theoretical basis for MLT to treat TBI patients. [Display omitted] •The up-regulated genes Mt1, Mt2, Il33, and Fth1 post-TBI were identified by transcriptome.•Melatonin, an agonist of MT1/2, inhibited inflammation and ferroptosis via MT2 and IL-33 pathways.•Fth depletion exacerbated inflammation and ferroptosis, except for IL-33 expression post-TBI.•Melatonin promoted the activation of CD206+ macrophage to exert anti-inflammation dependent on Fth.•Melatonin alleviated post-TBI edema and neurological outcomes by the MT2/IL-33/Fth signaling.