Chinese Medical Journal article reveals the potential of efferocytosis in mitigating stroke-induced brain damage

Stroke remains one of the leading causes of mortality worldwide, with ischemic stroke accounting for approximately 70–80% of cases. Ischemic stroke is characterized by the blockage of arteries that supply blood to the brain. The burden of this life-threatening condition continues to grow, driven by aging populations, lifestyle-related risk factors, and the lack of effective therapeutic options. This highlights the urgent need to uncover the pathological mechanisms underlying stroke-induced brain damage and identify novel therapeutic targets.

A collaborative research team from the Shanghai Jiao Tong University School of Medicine, Ulm University, Naval Medical University, and Loma Linda University conducted a comprehensive review examining the role of efferocytosis in stroke. Efferocytosis is a cellular mechanism involving the clearance of dead or dying cells called apoptotic cells—aiding in neurodevelopment and mitigating  inflammatory responses. Led by Dr. Qin Hu, their study was made available online on November 12, 2024 and was published in volume 132, issue 23  on December 5, 2024 of the Chinese Medical Journal. The review explores the role of efferocytosis in maintaining tissue homeostasis, its neuroprotective potential, and its therapeutic implications for stroke-induced brain injury.

During neurodevelopment, billions of neurons and synapses are formed, pruned, and refined to establish functional neural networks. "Efferocytosis is the process by which phagocytes recognize and remove apoptotic cells, which is essential for tissue homeostasis," explains Dr. Hu. Phagocytic cells such as microglia and astrocytes act as primary mediators, engulfing and removing cellular debris without triggering an inflammatory response. This process prevents inflammation and supports the maturation of neural circuits, ensuring proper brain development and optimal neural function.

Ischemic stroke, characterized by a reduction in cerebral blood flow, triggers widespread cell death and neuroinflammation. The efficient clearance of dead cells through efferocytosis is critical to mitigating secondary damage and fostering recovery. Studies suggest that enhancing efferocytosis may contribute to neuroprotection by resolving neuroinflammation, containing injury spread, and fostering an environment conducive to neural regeneration.

However, the dynamics of efferocytosis in ischemic conditions are intricate and not fully understood. While this mechanism typically aids in resolving inflammation, pathological conditions, such as ischemia, can impair its efficiency. This impairment leads to the accumulation of apoptotic cells, resulting in prolonged inflammation and exacerbation of brain damage.

"Microglia are the main immune cells of the brain. They are responsible for coordinating the innate immune response," notes Dr. Hu. These cells identify dying neurons and other cellular debris through "eat me" signals, such as phosphatidylserine, displayed on the surface of apoptotic cells. Specific receptors-like TAM (Tyro3, Axl and Mertk) receptors are associated with signaling proteins that enable microglia to accelerate the process of phagocytosis.

Efferocytosis has emerged as a promising therapeutic target for ischemic stroke. Potential strategies include enhancing efferocytosis through receptor modulation, mimicking "eat me" signals to boost cellular recognition or blocking inhibitory molecules that undermine the clearance process. Despite its potential, significant gaps in understanding remain. For instance, the precise molecular pathways regulating efferocytosis under ischemic conditions and its interactions with other neuroprotective mechanisms require further investigation.

Advancements in imaging technologies and molecular biology are expected to shed light on these mechanisms. Exploring the timing and regulation of efferocytosis in ischemic environments will be essential for optimizing its therapeutic application.

This review emphasizes the critical role of efferocytosis in inflammation resolution and its therapeutic potential for ischemic stroke. By deepening our understanding of efferocytosis, researchers aim to develop innovative strategies to minimize ischemic brain damage, promote recovery, and improve patient outcomes.

Taken together, these findings not only highlight the importance of efferocytosis but also open avenues for developing novel treatments that could transform the management of ischemic stroke. Dr. Hu concludes, "More in-depth studies on the mechanisms of efferocytosis after cerebral ischemia should be conducted to identify the potential strategies for targeting efferocytosis and thereby hindering ischemic insults and promoting neuronal regeneration."

Let us hope for innovative therapeutics to lessen the global burden of stroke through the meticulous understanding of the potential targets and the associated mechanisms.

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Reference

Titles of original papers: Efferocytosis: A new therapeutic target for stroke

Journal: Chinese Medical Journal

DOI: 10.1097/CM9.0000000000003363