The Role of Adipokines in Mediating Immuno-metabolic Crosstalk in Burn Sepsis

Authors:
Stephanie Wojtowicz-Piotrowski, Ghazaleh Dadashizadeh, Marc G. Jeschke

Body of Abstract:
Background: As the leading cause of mortality in burn injury, burn-induced sepsis drives extensive metabolic and immune dysregulation. However, how these metabolic and inflammatory pathways interact to shape disease progression remains unknown. Adipokines, signalling molecules released from adipose tissue, are essential for functional metabolism, and control processes such as inflammation, insulin sensitivity and energy homeostasis in the adipose tissue and distant organs. Emerging evidence suggests that these molecules interact closely with pro- and anti-inflammatory cytokines and can influence the progression of sepsis in non-burn-related contexts. However, it is unknown whether similar adipokine-cytokine interactions contribute to the pathophysiology of sepsis post-burn. Therefore, this study aims to identify whether such interactions exist in burn-induced sepsis.

Methods: Serum samples from non-septic and septic adult burn patients were analyzed using ELISA to quantify circulating levels of the adipokines leptin (LEP), adiponectin (ADIPOQ), and resistin (RETN). Cytokine profiles corresponding to the same patients were analyzed using Multiplex assays. Spearman correlation analyses were then performed to determine associations between adipokine and cytokine levels within non-septic and septic burn patient groups.

Results: Circulating adipokine profiles differed significantly between septic and non-septic burn patients. Serum LEP (p < 0.001) and RETN (p < 0.05) were significantly elevated, whereas ADIPOQ was significantly reduced (p < 0.05) in septic burn patients. In Spearman rank correlation analyses, surprisingly, neither LEP nor ADIPOQ demonstrated meaningful associations with any cytokines. Remarkably, however, RETN exhibited significant, positive correlations with nine different cytokines exclusively in septic burn patients: interleukin-10 (IL-10; rs=0.8929, p=0.01), IL-6 (rs=1, p=0.0004), granulocyte colony-stimulating factor (G-CSF; rs=0.8214, p=0.03), granulocyte-macrophage colony-stimulating factor (GM-CSF; rs=0.8857, p=0.03), IL-15 (rs =0.9643, p=0.003), IL-17 (rs=0.8571, p=0.02), IL-7, (rs=0.9643, p=0.003), IL-8 (rs=0.8571, p=0.02), and monocyte chemoattractant protein-1 (MCP-1; rs=0.8571, p=0.02). Conclusions: Here, our findings reveal RETN as a uniquely activated metabolic-immune signal in burn-induced sepsis. Unlike LEP or ADIPOQ, RETN demonstrated strong, sepsis-specific correlations with a broad network of pro- and anti-inflammatory cytokines, highlighting its potential mechanistic link between metabolic dysfunction and immune dysregulation after severe burn injury. Considering the diagnostic potential of cytokines in sepsis, the magnitude of these associations underscores the promise of RETN as both a potential diagnostic marker and therapeutic target. By uncovering this previously unrecognized adipokine-cytokine axis in burn sepsis, this study opens new avenues for targeted modulation of sepsis in burn patients.