Overview of the Role of RhoA/ROCK/NF-κB Pathway in Microglial Polarization after Ischemic Stroke

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In recent years, ischemic stroke has become one of the leading causes of death and disability worldwide. However, effective treatments for ischemic stroke are still lacking. Studies have shown that microglia, as resident macrophages in the central nervous system (CNS), are activated and polarized into pro-inflammatory or anti-inflammatory phenotypes in various brain injuries, including ischemic stroke. Pro-inflammatory microglia produce a variety of immune-regulatory mediators that are closely related to secondary brain injury after ischemic stroke; conversely, anti-inflammatory microglia contribute to post-stroke recovery. Therefore, regulating the activation and function of microglia is crucial for exploring new therapeutic approaches for ischemic stroke patients. The RhoA/ROCK pathway and NF-κB act as key regulators in microglial activation and polarization processes, and inhibiting these regulators can promote microglial polarization towards an anti-inflammatory phenotype.

Authors and Source Introduction

This article was co-authored by Weizhuo Lu, Yilin Wang, and Jiyue Wen, three pharmacology experts from Anhui Medical University. The paper was published in the Journal of Neuroimmune Pharmacology in 2024.

Research Background and Motivation

The main pathological mechanisms of ischemic stroke include neuronal oxygen-glucose deprivation, neuroinflammation, blood-brain barrier (BBB) disruption, and brain injury. As resident immune cells in the CNS, microglia exhibit prominent inflammatory responses during stroke. Studies have shown that microglial activation and polarization play important roles in the pathological process of stroke, with the presence of pro-inflammatory microglia exacerbating neuroinflammation and brain injury, while anti-inflammatory microglia help to alleviate inflammation and promote neuronal repair. Therefore, understanding the mechanisms of microglial polarization is of great significance for developing new therapies for stroke.

Research Content and Workflow

This article reviews the role of the RhoA/ROCK/NF-κB signaling pathway in microglial activation and polarization after ischemic stroke, as well as the research progress of related drug modulators.

Microglial Polarization

In the acute phase of ischemic stroke, microglia rapidly respond to ischemic stress and neuronal damage, exhibiting morphological and functional changes. Microglia are generally classified into pro-inflammatory (neurotoxic) and anti-inflammatory (neuroprotective) phenotypes. Pro-inflammatory microglia exacerbate brain injury by releasing pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF-α), while anti-inflammatory microglia promote neuronal repair by releasing anti-inflammatory factors (such as IL-10 and TGF-β).

RhoA/ROCK Pathway

RhoA is a member of the Rho family of small GTPases, and ROCK is its main downstream effector. The RhoA/ROCK pathway plays important roles in cell contraction, migration, and neuronal proliferation and regeneration. Studies have shown that activation of the RhoA/ROCK pathway is closely associated with neuroinflammation and blood-brain barrier disruption in stroke. In microglia, the RhoA/ROCK pathway regulates their migration and polarization processes.

NF-κB Pathway

NF-κB is a family of inducible transcription factors involved in the release of inflammatory mediators and regulation of gene expression. After stroke injury, NF-κB is activated and translocates from the cytoplasm to the nucleus, promoting the release of pro-inflammatory cytokines. There are two main signaling pathways of NF-κB: the classical pathway and the non-classical pathway. The classical pathway is mainly mediated by the p50/p65 heterodimer, which binds to IκB to inhibit its activity, and is subsequently activated by phosphorylation of the IκB kinase (IKK) complex under stimulation of pro-inflammatory factors. The non-classical pathway is mainly through the activation of NF-κB-inducing kinase (NIK), promoting the nuclear translocation of RelB/p52 dimers.

Relationship between RhoA/ROCK and NF-κB Pathways

The RhoA/ROCK and NF-κB pathways are closely related in regulating microglial polarization. Activation of the RhoA/ROCK pathway can promote NF-κB activation, enhancing pro-inflammatory microglial polarization and inflammatory responses. By inhibiting the RhoA/ROCK pathway, NF-κB activation can be blocked, reducing pro-inflammatory microglial polarization and thus alleviating brain injury.

Drug Modulators

Studies have shown that many drugs can achieve anti-stroke effects by regulating microglial polarization and neuroinflammation. For example, Fingolimod and Rosiglitazone regulate microglial polarization towards an anti-inflammatory phenotype by inhibiting the NF-κB pathway. In addition, traditional Chinese medicines such as Parthenolide and Hesperetin have also shown effects in regulating microglial polarization and alleviating neuroinflammation.

Conclusion

In summary, this article systematically reviews the important role of the RhoA/ROCK/NF-κB pathway in microglial polarization after ischemic stroke, revealing the interrelationship between RhoA/ROCK and NF-κB in regulating microglial phenotypes. These findings have important implications for developing new therapeutic targets for ischemic stroke. By regulating these key signaling pathways, control of microglial polarization can be achieved, thereby alleviating post-stroke neuroinflammation and promoting brain injury repair.

Significance and Prospects

The article also points out that although various drugs have shown potential in regulating microglial polarization in experimental studies, clinical research is still insufficient. Future studies need to further explore the efficacy and safety of these drugs in clinical applications, providing new ideas and strategies for the treatment of ischemic stroke. Through in-depth research on the RhoA/ROCK/NF-κB pathway and its modulators, it is hoped that more effective treatment methods can be brought to ischemic stroke patients.