Serum Microtubule-Associated Protein Light Chain 3 Type II Levels Correlate with Aggravation and Multi-Organ Dysfunction in Septic Patients
Sepsis is a life-threatening condition characterized by dysregulated host responses to infection, involving both pro- and anti-inflammatory pathways, as well as significant alterations in non-immunologic processes. Autophagy, a lysosome-dependent mechanism for clearing damaged cellular components, has emerged as a critical protective mechanism in sepsis. Experimental studies suggest that impaired autophagy during later stages of sepsis correlates with poor outcomes, highlighting its potential as a therapeutic target. However, the clinical utility of autophagy-related biomarkers for guiding sepsis management remains underexplored. This study investigates serum levels of microtubule-associated protein light chain 3 type II (LC3b), a key autophagy marker, in relation to disease severity, organ dysfunction, and inflammatory responses in septic patients.
Study Design and Patient Stratification
A prospective cohort study was conducted at Peking Union Medical College Hospital from June 2019 to August 2020, enrolling 163 patients within 24 hours of intensive care unit (ICU) admission. Patients were stratified into three groups based on disease progression:
- Infection group (n = 29): Patients with active or suspected infection but no sepsis criteria.
- Septic nonshock group (n = 40): Patients meeting Sepsis-3 criteria (acute increase in Sequential Organ Failure Assessment [SOFA] score ≥2 points due to infection) without shock.
- Septic shock group (n = 94): Patients requiring vasopressors to maintain mean arterial pressure ≥65 mmHg and serum lactate >2 mmol/L.
Exclusion criteria included age <18 years, recent major cardiovascular events, or lack of informed consent. Clinical parameters such as SOFA, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, vasopressor use, lactate, and procalcitonin (PCT) levels were recorded. The primary outcome was ICU mortality or discharge.
Key Findings on LC3b and Disease Severity
Serum LC3b levels were quantified using enzyme-linked immunosorbent assay (ELISA) and analyzed across groups. The infection group exhibited the highest LC3b levels (median: 344.66 pg/mL), followed by the septic nonshock (median: 253.83 pg/mL) and septic shock groups (median: 219.99 pg/mL) (Figure 1A). This progressive decline in LC3b with worsening sepsis severity (p < 0.001) aligns with preclinical evidence suggesting early autophagy activation as a protective response, followed by suppression in advanced disease.
Non-survivors showed lower LC3b levels (median: 227.74 pg/mL) compared to survivors (median: 253.83 pg/mL), though this difference was not statistically significant (p = 0.069), potentially due to limited sample size. LC3b levels also inversely correlated with SOFA scores (r = -0.609, p < 0.001), APACHE II scores (r = -0.260, p < 0.01), and PCT levels (r = -0.311, p < 0.001), underscoring its association with organ dysfunction and disease severity.
Autophagy and Inflammatory Cytokine Regulation
To explore the interplay between autophagy and inflammation, serum levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) were measured. Patients with LC3b levels above the median (263.92 pg/mL) demonstrated significantly lower IL-1β (12.67 vs. 21.54 pg/mL, p < 0.001) and IL-18 (168.21 vs. 246.32 pg/mL, p < 0.001) compared to those below the median (Figure 1B). This supports the hypothesis that autophagy mitigates excessive inflammation by regulating inflammasome activity and cytokine release.
Clinical and Pathophysiological Implications
The study highlights LC3b as a dynamic biomarker reflecting autophagic activity during sepsis progression. Elevated LC3b in early infection suggests compensatory autophagy activation to limit cellular damage and pathogen spread. Conversely, declining LC3b in septic shock may indicate autophagic suppression, contributing to organ failure and adverse outcomes. The correlation between LC3b and SOFA scores further positions it as a potential tool for real-time monitoring of multi-organ dysfunction.
Notably, LC3b levels did not differ significantly between patients with gram-negative versus gram-positive infections (p = 0.055), suggesting its role as a universal indicator of autophagic flux rather than a pathogen-specific marker.
Limitations and Future Directions
While this study provides critical insights, several limitations must be addressed. The single-center design and modest sample size may limit generalizability. Additionally, the observational nature precludes establishing causality between autophagy suppression and outcomes. Future multicenter studies with larger cohorts are needed to validate LC3b’s prognostic utility and explore its responsiveness to therapies targeting autophagy.
Conclusion
This study establishes serum LC3b as a clinically relevant biomarker of autophagy in sepsis, with levels inversely correlating with disease severity, organ dysfunction, and proinflammatory cytokine release. The findings underscore autophagy’s dual role in sepsis—protective in early stages and decompensated in advanced disease—and advocate for further research into autophagy-modulating therapies.
doi.org/10.1097/CM9.0000000000001640
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