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GAS6/AXL Boosts M2 Microglia to Ease Sepsis Brain Inflammation

June 6, 2025
in Medicine
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In a groundbreaking study published in Cell Death Discovery, researchers have unveiled new insights into the molecular mechanisms that regulate neuroinflammation in sepsis-associated encephalopathy (SAE), a severe and often fatal complication of sepsis affecting the brain. The study highlights the pivotal role of the GAS6/AXL signaling pathway in promoting the efferocytosis function of M2 microglia, thereby mitigating neuroinflammatory damage. These findings open potential therapeutic avenues for combating SAE, a condition that currently lacks effective treatments and presents substantial clinical challenges worldwide.

Sepsis-associated encephalopathy represents a diffuse cerebral dysfunction triggered by systemic infection and inflammation, characterized by delirium, cognitive deficits, and long-term neurological impairment. Central to this pathology is an overactive immune response that compromises the delicate homeostasis of the central nervous system (CNS). Microglia, the brain-resident macrophages, orchestrate the neuroimmune response, modulating inflammation, clearing cellular debris, and maintaining neural circuitry integrity. Among microglial phenotypes, the alternatively activated M2 type is associated with anti-inflammatory and reparative functions. Understanding how these microglia coordinate efferocytosis—the process of engulfing and removing apoptotic cells—has remained a critical gap until now.

The researchers focused on the GAS6 (growth arrest-specific 6) protein and its receptor, AXL, a receptor tyrosine kinase belonging to the TAM family, known to regulate immune homeostasis and cell clearance. Prior studies had hinted at the GAS6/AXL axis’s involvement in diverse inflammatory settings, but its precise role within the CNS microenvironment during sepsis remained elusive. Through a combination of in vivo and in vitro experiments utilizing murine models of sepsis and primary microglial cultures, the study delineated how GAS6 binding to AXL on M2 microglia dramatically enhanced their efferocytic capacity.

Mechanistically, activation of AXL triggered downstream signaling cascades, including the PI3K/Akt and ERK pathways, which are vital for cytoskeletal remodeling and phagosome formation. These intracellular events facilitated the efficient recognition, engulfment, and degradation of apoptotic neurons and cellular debris resulting from sepsis-induced brain injury. Notably, inhibiting the GAS6/AXL axis suppressed efferocytosis, exacerbating neuroinflammation and neurodegeneration, thereby underscoring its protective role. This phenomenon was accompanied by a reduction in pro-inflammatory cytokines such as IL-1β and TNF-α and an increase in anti-inflammatory mediators like IL-10, indicating a balanced immune milieu fostered by GAS6/AXL signaling.

One of the notable strengths of this work lies in its detailed dissection of microglial polarization dynamics. By leveraging flow cytometry, immunohistochemistry, and gene expression analyses, the investigators demonstrated that the GAS6/AXL pathway preferentially enhanced M2 microglial phenotypes while dampening pro-inflammatory M1 characteristics. This shift was crucial in containing the deleterious effects of systemic inflammation on brain tissue. Furthermore, the study revealed temporal nuances where GAS6/AXL activation was most pronounced during the acute phases of sepsis, highlighting a window of opportunity for therapeutic intervention.

In addition to advancing molecular understanding, the researchers explored translational potential by administering recombinant GAS6 protein to septic animal models. Treatment not only augmented microglial efferocytosis but also significantly improved neurological outcomes, measured through behavioral assays assessing motor coordination and cognitive functions. These promising results set a precedent for future clinical trials aimed at harnessing GAS6/AXL signaling to treat SAE patients.

Sepsis-associated encephalopathy remains poorly understood, partly due to the complexity of immune-brain interactions and the heterogeneity of patient presentations. This study’s comprehensive approach combining molecular biology, neuroimmunology, and in vivo modeling offers a robust framework to unravel these complexities. The identification of GAS6/AXL as a key regulator of neuroprotective microglial functions presents a paradigm shift, moving beyond systemic infection control toward targeted modulation of CNS immunity.

The implications of these findings extend beyond sepsis, potentially influencing therapeutic strategies for other neuroinflammatory disorders such as Alzheimer’s disease, multiple sclerosis, and traumatic brain injury, where aberrant microglial activation plays a detrimental role. By restoring efferocytosis and fostering tissue repair, manipulation of the GAS6/AXL pathway could represent a universal mechanism to modulate CNS inflammation safely.

Importantly, the study carefully considered the safety profile of manipulating GAS6/AXL signaling. Given AXL’s involvement in cancer progression and immune evasion in tumors, the authors emphasize the need for precise targeting and timing in potential therapies to avoid unintended oncogenic effects. Nonetheless, the CNS-specific delivery and localized activation strategies could mitigate such risks, making GAS6/AXL modulation a viable therapeutic target with minimal systemic adverse effects.

This research also paves the way for biomarker development. Elevated levels of GAS6 or soluble AXL in cerebrospinal fluid or blood could serve as diagnostic indicators for the severity of SAE or treatment efficacy. Such biomarkers would be invaluable in the clinical setting for patient stratification, prognosis, and monitoring therapeutic responses in real time.

In conclusion, the elucidation of the GAS6/AXL signaling axis as a promoter of M2 microglial efferocytosis marks a significant advance in understanding neuroimmune crosstalk during sepsis-associated encephalopathy. By harnessing this pathway, future therapies may significantly reduce the burden of cognitive impairment and mortality associated with sepsis-related brain dysfunction. Continued research into the molecular intricacies and translational applications of this pathway will undoubtedly reshape approaches to managing sepsis and other devastating neuroinflammatory conditions.

As the scientific community strives to combat the global burden of sepsis and its neurological complications, discoveries such as these offer hope for novel, mechanism-based interventions that enhance the body’s innate ability to heal the brain. The GAS6/AXL axis stands out as a beacon in this landscape, illuminating new frontiers in neuroimmunology and clinical neuroscience.


Subject of Research: GAS6/AXL signaling and its role in promoting M2 microglial efferocytosis to alleviate neuroinflammation in sepsis-associated encephalopathy.

Article Title: GAS6/AXL signaling promotes M2 microglia efferocytosis to alleviate neuroinflammation in sepsis-associated encephalopathy.

Article References: Tang, Y., Hu, H., Xie, Q. et al. GAS6/AXL signaling promotes M2 microglia efferocytosis to alleviate neuroinflammation in sepsis-associated encephalopathy. Cell Death Discov. 11, 268 (2025). https://doi.org/10.1038/s41420-025-02507-8

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02507-8

Tags: brain inflammation managementcognitive deficits in sepsisefferocytosis in microgliaGAS6 AXL signaling pathwayimmune response in CNSM2 microglia functionmicroglial phenotypes and functionsneuroimmune interactionsneuroinflammation in sepsissepsis-associated encephalopathytherapeutic targets for SAEtreatment challenges for sepsis-related brain injury
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