Mcl-1 protects eosinophils from apoptosis and exacerbates allergic airway inflammation

Abstract

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.

The multiple mechanisms of MCL1 in the regulation of cell fate

“…These studies found that transcriptional silencing of MCL1 through CDK inhibitors promotes neutrophil apoptosis, while sparing macrophages and the phagocytosis of neutrophils 42 . In a separate study, AT7519 was shown to sensitize resistant eosinophils to apoptosis in mice transgenically overexpressing MCL1 40 . Significantly, these studies suggest a therapeutic opportunity for targeting MCL1 in inflammatory conditions as it promotes the resolution of neutrophils and eosinophils while sparing other lineages of the host immune system.…”

“…Moreover, while not specifically responsible for macrophage cell survival in vivo, MCL1 modulates the macrophage effector response during bacterial phagocytosis, where the knockdown of MCL1 enhances sensitivity to macrophage cell death 32 , 39 . Phagocytes generally not only coordinate acute inflammation but also can cause inflammatory tissue damage through neutrophil recruitment or reduced eosinophil apoptosis 40 . Recently, the overexpression of MCL1 has been reported to exacerbate allergic airway inflammation and resist eosinophilic apoptosis 40 .…”

“…Phagocytes generally not only coordinate acute inflammation but also can cause inflammatory tissue damage through neutrophil recruitment or reduced eosinophil apoptosis 40 . Recently, the overexpression of MCL1 has been reported to exacerbate allergic airway inflammation and resist eosinophilic apoptosis 40 . To this end, targeting MCL1 in inflammatory lung conditions that induce acute respiratory distress or allergic airway disease, such as eosinophilic asthma, has been evaluated using the cyclin-dependent kinase (CDK) inhibitor AT7519 [40][41][42] .…”

“…Recently, the overexpression of MCL1 has been reported to exacerbate allergic airway inflammation and resist eosinophilic apoptosis 40 . To this end, targeting MCL1 in inflammatory lung conditions that induce acute respiratory distress or allergic airway disease, such as eosinophilic asthma, has been evaluated using the cyclin-dependent kinase (CDK) inhibitor AT7519 [40][41][42] . These studies found that transcriptional silencing of MCL1 through CDK inhibitors promotes neutrophil apoptosis, while sparing macrophages and the phagocytosis of neutrophils 42 .…”

Understanding MCL1: from cellular function and regulation to pharmacological inhibition

“…Therefore, this study provides evidence that small molecule inhibitors of MCL1 may represent a possible therapeutic avenue for treating ischemic stroke in human patients. Additionally, Felton et al linked the overexpression of the human form of MCL1 in mice with the exacerbation of allergic airway inflammation, with increased cellularity of bronchoalveolar lavage fluid, eosinophil number, total protein, and airway mucus production observed [119].…”