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The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network

ABSTRACT: MLKL, as the executor of necroptosis and a critical factor in the inflammation, has been shown to be associated with the progression of hemorrhagic stroke. Studies identified MLKL is a promoting factor in this process, suggesting its potential as a therapeutic target to mitigate post-hemorrhagic stroke damage. However, there is no direct evidence supporting MLKL as a drug target for hemorrhagic stroke currently, and the precise mechanisms by which MLKL functions in this context remain unclear. Here, we established an intracerebral hemorrhage model by collagenase IV injection and found that MLKL knockout alone was insufficient to fully reverse neuroinflammation and pathological damage. To further elucidate the molecular mechanisms underlying the effects of MLKL knockout on the ICH model, we conducted a proteomic analysis via LC-MS/MS. While MLKL knockout did not significantly reverse the damage caused by intracerebral hemorrhage, enhanced pathways related to inflammation, metabolism, and coagulation as well as attenuated functions related to neuron assemble were identified, suggesting that MLKL may exert its effects through these pathways. Based on these findings, we hypothesize that co-targeting MLKL and its associated protein network may yield better therapeutic outcomes for hemorrhagic stroke.

ORGANISM(S): Mus Musculus

SUBMITTER: Jingbo Qie

PROVIDER: PXD056595 | iProX | Fri Sep 27 00:00:00 BST 2024

REPOSITORIES: iProX

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Project description:The etiology of trauma-hemorrhage shock-induced acute lung injury has been difficult to elucidate due, at least in part, to the inability of in vivo studies to separate the non-injurious pulmonary effects of trauma-hemorrhage from the tissue injurious ones. To circumvent this in vivo limitation, we utilized a model of trauma-hemorrhagic shock (T/HS) in which T/HS-lung injury was abrogated by dividing the mesenteric lymph duct. In this way, it was possible to separate the pulmonary injurious response from the non-injurious systemic response to T/HS by comparing the pulmonary molecular response of rats subjected to T/HS which did and did not develop lung injury as well as to non-shocked rats. Utilizing high-density oligonucleotide arrays and treatment group comparisons of whole lung tissue collected at 3 hours after the end of the shock or sham-shock period, 139 of the 8,799 assessed genes were differentially expressed. Experiment Overall Design: Four groups of rats (n=3) were studied in order to identify changes in pulmonary gene expression associated with T/HS, both in the presence and absence of lung injury. These included trauma-sham shock (T/SS) rats which had a laparotomy (trauma) but were not subjected to hemorrhagic shock. These rats had no lung injury and served as controls for rats which were subjected to T/HS (laparotomy plus 90 min of shock) and had lung injury. Differences in gene expression between these two groups would represent both the effects of hemorrhagic shock as well as lung injury. To distinguish the gene response of hemorrhagic shock from the gene response associated with lung injury, gene expression was also compared between T/HS rats (hemorrhage and lung injury) and rats subjected to T/HS plus lymph duct ligation (T/HS-LDL), since the T/HS-LDL rats experienced hemorrhagic shock but had no measurable lung injury. Lastly, to identify hemorrhagic shock- modified genes, the pulmonary gene response of T/HS-LDL (hemorrhage without lung injury) were compared to rats subjected to T/SS plus LDL (no hemorrhage or lung injury). Three hours after the end of the 90 min shock or sham-shock period (i.e. 4.5 hrs after the induction of T/HS), the rats were sacrificed and specimens harvested for genechip analysis and histology.

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The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network

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