Kristina Shkirkova, BSc
Yan J, Xu W, Lenahan C, Huang L, Wen J, Li G, Hu X, Zheng W, Zhang JH, Tang J. CCR5 Activation Promotes NLRP1-Dependent Neuronal Pyroptosis via CCR5/PKA/CREB Pathway After Intracerebral Hemorrhage. Stroke. 2021.
Intracerebral hemorrhage (ICH) is the most debilitating stroke subtype, resulting in higher mortality and disability than ischemic stroke. The mechanism of vessel rapture results in blood leaking into the brain tissue, leading not only to physical damage to the surrounding tissue, but also triggering a severe acute inflammatory response in the brain. Acute inflammation is driven by several inflammatory cytokines and inflammasomes that initiate cellular pathways of pyroptosis that ultimately result in neuronal death.
In this study, the authors focused on a neuronal cell death pathway that involves C-C chemokine receptor 5 (CCR5), which is located in the cell membrane and regulates leukocytes transport in the cells. Using mice with induced IHC, the authors targeted deactivation of this receptor to reduce the inflammatory response in the brain using an antagonist agent to CCR5. After 1 hour of induced ICH in mice, CCR5 antagonist treatment resulted in reduced number of neuronal cells undergoing degeneration and death at 24 and improved neurological motor and sensorimotor functioning at 24 and 72 hours. CCR5 antagonist treatment also significantly increased protein kinase A (PKA) and cAMP response element binding protein (CREB) levels.
To further study the mechanisms of this pathway, the authors treated mice with CREB inhibitor 666-15 before CCR5 antagonist treatment. There was a reversal of the previously observed effects of the CCR5 antagonist on the cellular and functional outcomes. This suggests a downstream role of the CREB signaling in the CCR5 antagonist-mediated pyroptosis-inhibiting response observed previously. Additionally, activation of CCR5 in the brain with recombinant C-C chemokine ligand 5 (rCCL5) resulted in decreased PKA a and CREB protein levels but increased inflammatory and pyroptosis markers. This pro-inflammatory effect was in turn reversed by administration of 8-Bromo-cAMP, which upregulated the expression of PKA and CREB protein levels. These results suggest that PKA is upstream of CREB activation after ICH. Overall, this series of experiments presented in this article show that inhibiting CCR5 pathway reduced neuronal death by pyroptosis with recruitment of PKA and CREB signaling.
Although the role of this pathway is important in the ICH associated neuronal death, there are other forms of neuronal cell death guided by intracellular and extracellular programs such as apoptosis and necrosis. CCR5 pathway may not be limited to the process of pyroptosis only, and its complexity requires further investigation.
In conclusion, reducing levels of acute inflammation immediately after intracranial hemorrhage has a direct effect on improving neurological outcomes in mice. This suggests that early interventions in humans that target inflammatory pathways have a potential to improve outcomes after intracerebral hemorrhage.