Biochemical and Biophysical Research Communications
TREM-1-targeting LP17 attenuates cerebral ischemia-induced neuronal injury by inhibiting oxidative stress and pyroptosis
Introduction
Ischemic stroke is one of the most common cerebrovascular diseases and a leading cause of disability and mortality in adults worldwide [1]. Microglial are mononuclear phagocytic cells in the central nervous system. They are important cellular mediators of neuroinflammation after cerebral infarction [2]. Following ischemia damage, microglial are rapidly activated and undergo phenotypic and morphological changes [3]. Several studies focused on the basic regulation mechanism of microglial activation which results in the secretion of pro-inflammatory cytokines [4], and also promote protective microglial to secret anti-inflammatory cytokines, such as IL-10 [5]. However, anti-inflammatory treatments have been tested in clinical trials, but the expected outcomes in ischemic stroke have not yet been disclosed [6]. Therefore, there is a need to investigate the molecular mechanism of microglial activation in cerebral infarction.
Pyroptosis is a form of programmed necrosis triggered by caspase-1 activation in NLRP3 inflammasomes. It is distinct from other forms of cell death since it is associated with the activation of inflammasomes and mediated by gasdermin D (GSDMD) [7]. Pyroptosis also plays a critical role in the pathogenesis of cerebrovascular diseases, such as ischemia damage [8]. The NLRP3 inflammasomes are assembled and activated following cerebral ischemic/reperfusion (I/R) injury and results in activation of GSDMD [9]. Cerebral infarction is also associated with various complicated pathological processes, including oxidative stress and inflammation [10]. During ischemia, nitric oxide (NO) and hydroxyl free radicals are generated, which can cause ROS accumulation, inflammation, and pyroptosis [11,12]. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a recently discovered cell surface receptor and a member of the extracellular immunoglobulin family. TREM-1 engagement triggers the synthesis and release of pro-inflammatory cytokines [13]. Previous studies have shown that TREM-1 plays a critical role in diseases, such as myocardial infarction and atherosclerosis [14,15]. Moreover, inhibiting TREM-1 reduces the pro-inflammatory cytokine release and activation of pyroptosis by decreasing ROS accumulation in acute lung injury [16]. However, the effect of TREM-1 and its downstream consequences on neuroinflammation following ischemic stroke needs further investigation.
In this study, we investigated whether microglial TREM-1 mediates neuroinflammation following ischemic damage and if the involvement is through interaction with oxidative stress and pyroptosis.
Section snippets
Animals models
All the animal studies were conducted according to the guidelines of the Animal Care and use Committee of Jinan University. Sprague Dawley rats aged 3 months old and weighing between 300 and 350 g were supplied by the Guangdong Medical Laboratory Animal Center. The rats were anesthetized with a 10% chloral hydrate (3 ml/kg, BBI, China) (i.p.) solution and MCAO model established as previously described [17]. TREM-1 inhibitory peptide LP17 (1 mg/kg, GenScript, China) was intranasally administered
TREM-1 expression is induced following MCAO in rats
Fluoro-Jade B (FJB) staining was significantly increased 12 h after operation, and the expression peaked at 3 d in the peri-infarct regions after MCAO. This revealed the degenerated neurons and activated microglial triggered by MCAO (Fig. 1A). TREM-1 mRNA and protein expression levels were progressively elevated in the peri-infarct regions, especially at 3 d after MCAO (Fig. 1C–E). Immunofluorescent results showed that the TREM-1 expression was higher compared with the sham rats after MCAO
Discussion
In this study, inhibition of TREM-1 ameliorated neurological deficit scores and reduced ischemic brain damage. Interestingly, TREM-1 was found to be a significant target molecule involved in neuronal damage caused by microglial activation in ischemia. This was associated with the inhibition of oxidative stress and pyroptosis. These findings strongly suggest that inhibiting TREM-1 may be used as a prospective neuroprotective mechanism and LP17 is a promising agent against cerebral I/R damage.
Declaration of competing interest
We declare that none of the work contained in this manuscript is published in any language or currently under consideration at any other journal, and there are no conflicts of interest to declare. All authors have contributed to, read, and approved this submitted manuscript in its current form.
Acknowledgements
This work was supported by the Natural Science Foundation of Guangdong Province (2020A1515011249), and the National Natural Science Foundation of China (81171084).
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These authors contributed equally to this work.