image: Cellular death within the infarcted core occurs rapidly due to energy depletion, resulting in the release of DAMPs such as HMGB1, ATP, and HSPs. These DAMPs engage pattern recognition receptors, including Toll-like receptors (TLR2 and TLR4) and scavenger receptors, thereby initiating innate immune responses. For instance, the interaction of HMGB1 with TLR4 activates the NF-κB signaling pathway, which subsequently induces the expression of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. This cascade promotes the infiltration of peripheral immune cells, leading to disruption of the blood-brain barrier, exacerbation of cerebral edema, and neuronal cell death. Concurrently, ROS generated from mitochondrial damage further amplify inflammatory signaling through oxidative stress, establishing a detrimental feedback loop. Conversely, a moderate inflammatory response is essential for tissue repair and functional recovery. Anti-inflammatory cytokines, including IL-10 and TGF-β, play a pivotal role in mitigating excessive inflammation, thereby facilitating nerve regeneration and angiogenesis. The figure was generated using Figdraw (https://www.figdraw.com/ ). ATP, adenosine triphosphate; DAMPs, damage-associated molecular patterns; HMGB1, high mobility group protein B1; HSPs, heat shock proteins; IL, interleukin; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species; TGF-β, transforming growth factor-beta; TLR2, Toll-like receptor 2; TNF-α, tumor necrosis factor-alpha.
Credit: Shun Li, Tianqing Xiong
Ischemic stroke, a leading cause of disability and mortality worldwide, is a complex cerebrovascular event with outcomes heavily influenced by the inflammatory response. This response, triggered by cerebral ischemia, plays a critically dual role: while exacerbating secondary damage in the acute phase, it is also essential for tissue repair and recovery. The identification and study of inflammation-related biomarkers have thus emerged as a pivotal area of research, offering new avenues for early diagnosis, prognostic assessment, and targeted therapy in the pursuit of precision medicine for stroke.
The Dual-Nature Inflammatory Response Post-Stroke
The inflammatory cascade begins with the release of damage-associated molecular patterns (DAMPs) from dying neurons in the infarct core. These DAMPs activate innate immune pathways, such as Toll-like receptors (TLRs) and the NF-κB signaling pathway, leading to a surge in pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6. This response promotes the infiltration of peripheral immune cells, disrupts the blood-brain barrier (BBB), and amplifies oxidative stress, causing further neuronal death. Conversely, a moderated inflammatory response, driven by anti-inflammatory cytokines like IL-10 and TGF-β, is crucial for facilitating nerve regeneration and angiogenesis, highlighting the need for balanced therapeutic intervention.
Key Inflammatory Biomarkers and Their Mechanisms
The review systematically categorizes and explains the roles of various biomarkers:
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Cytokines and Chemokines: IL-6, TNF-α, and IL-1β are key drivers of acute neuroinflammation, with their dynamic levels correlating with stroke severity, infarct volume, and prognosis. The CCL19/CCR7 axis, in particular, has been identified as critical for mediating T cell infiltration into the central nervous system, directly impacting secondary injury.
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Acute-Phase Proteins: C-reactive protein (CRP) is a well-established biomarker whose rapid elevation post-stroke assists in diagnosis, differential diagnosis of stroke subtypes, and prognostic evaluation. Other proteins like serum amyloid A and fibrinogen also contribute to the pathophysiology.
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Matrix Metalloproteinases (MMPs): MMPs, especially MMP-9, have a time-dependent role. In the acute phase, they contribute to BBB disruption and hemorrhagic transformation. Later, they facilitate tissue remodeling and repair, though excessive activity can be detrimental.
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Novel Biomarkers:
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MicroRNAs (miRNAs): These small non-coding RNAs exhibit dual functions. For instance, miR-126 protects BBB integrity, while miR-155 exacerbates it. Their rapid changes in serum post-stroke make them promising diagnostic tools and therapeutic targets (e.g., miR-15a/16-1 antagonists).
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Galectin-3 (Gal-3): Released by activated microglia, Gal-3 promotes inflammation via the TLR-4/NF-κB pathway. Elevated serum Gal-3 levels are independently associated with poor 90-day outcomes, and its inhibitors are under investigation.
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Clinical Applications
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Diagnosis: Biomarkers like IL-6, CRP, and MMP-9 rise within hours of stroke onset, aiding early diagnosis. Furthermore, specific inflammatory profiles can help distinguish between stroke subtypes (e.g., atherosclerotic vs. cardioembolic), forming a basis for personalized treatment.
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Prognostic Evaluation: Elevated levels of CRP, IL-6, and MMP-9 are consistently correlated with poorer neurological recovery and increased mortality. Ratios such as the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) are powerful, readily available predictors of complications like stroke-associated pneumonia and poor functional outcomes.
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Guiding Thrombectomy: Inflammatory biomarkers provide crucial insights for endovascular thrombectomy (EVT). Pre-operative SII and post-operative NLR can predict poor prognosis, while the fibrinogen-to-albumin ratio (FAR) indicates the risk of hemorrhagic transformation. Monitoring CCR7+ T cell frequency may help identify an active neuroinflammatory phase, guiding the timing of intervention to minimize reperfusion injury.
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Therapeutic Potential: Inflammatory pathways are promising therapeutic targets. Monoclonal antibodies against IL-1β, MMP inhibitors, and agents that modulate microglial polarization are being explored. The future lies in multi-target combination therapies and using biomarker profiles to guide individualized treatment plans, balancing anti-inflammatory effects with the needs of tissue repair.
Challenges and Future Directions
Despite the promise, significant challenges remain. The complexity and dynamism of inflammation mean single-target interventions may be insufficient. There is a need to balance suppressing harmful inflammation while preserving reparative processes. Future research must focus on standardizing detection methods, validating biomarkers in large-scale trials, developing multi-marker diagnostic and prognostic models, and advancing targeted delivery systems (e.g., using exosomes for miRNA therapy).
Conclusion
The inflammatory response is a cornerstone of ischemic stroke pathophysiology. The comprehensive investigation of inflammatory biomarkers—from classical cytokines to novel miRNAs and Gal-3—provides profound insights for revolutionizing stroke management. These biomarkers are poised to play an increasingly critical role in enabling early diagnosis, accurate prognosis, and the development of precision medicine strategies, ultimately improving patient outcomes.
Full text:
https://xiahepublishing.com/3067-6150/NSSS-2025-00029
The study was recently published in the Neurosurgical Subspecialties.
Neurosurgical Subspecialties (NSSS) is the official scientific journal of the Department of Neurosurgery at Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. NSSS aims to provide a forum for clinicians and scientists in the field, dedicated to publishing high-quality and peer-reviewed original research, reviews, opinions, commentaries, case reports, and letters across all neurosurgical subspecialties. These include but are not limited to traumatic brain injury, spinal and spinal cord neurosurgery, cerebrovascular disease, stereotactic radiosurgery, neuro-oncology, neurocritical care, neurosurgical nursing, neuroendoscopy, pediatric neurosurgery, peripheral neuropathy, and functional neurosurgery.
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Journal
Neurosurgical Subspecialties
Article Title
Inflammatory Biomarkers in Ischemic Stroke: Mechanisms, Clinical Applications, and Future Directions
Article Publication Date
4-Oct-2025