Leukocytes and Inflammatory Signaling in Laminitis: Inflammatory Signaling
Authors: Leise Britta
Journal: Equine Laminitis
Summary
# Editorial Summary: Leukocytes and Inflammatory Signaling in Laminitis Hyperinsulinaemia drives a distinct inflammatory pathway in equine metabolic syndrome-associated laminitis (EMSAL) that differs fundamentally from sepsis-triggered disease, yet the precise molecular mechanisms remain poorly characterised. Leise (2017) induced hyperinsulinaemia in 16 healthy Standardbred horses using a euglycemic-hyperinsulinaemic clamp protocol, collecting digital lamellar tissue at 48 hours or upon onset of Obel grade 1 laminitis to profile inflammatory gene expression, intracellular signalling proteins, and leukocyte infiltration patterns. Hyperinsulinaemic horses demonstrated upregulation of IL-1β, IL-6, IL-11, COX-2 and E-selectin transcripts, alongside increased phosphorylation of STAT1 and STAT3 proteins localised to basal epithelial cell nuclei, yet notably absent were elevated neutrophil chemoattractants (CXCL1, CXCL6, CXCL8) and minimal lamellar leukocyte infiltration. This STAT-mediated inflammatory signalling without substantial neutrophil recruitment represents a fundamentally different pathophysiology from classical sepsis-associated laminitis, suggesting that metabolic laminitis involves direct epithelial cell signalling dysregulation rather than innate immune cell-driven inflammation. For practitioners, these findings reinforce that EMSAL management should prioritise metabolic control and direct anti-inflammatory strategies rather than assuming mechanisms analogous to endotoxaemic laminitis.
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Practical Takeaways
- •Metabolic laminitis involves a distinct inflammatory pathway driven by STAT signaling rather than acute leukocyte infiltration, potentially explaining why anti-inflammatory strategies effective in septic laminitis may need modification for metabolic cases
- •Early detection of hyperinsulinemia and aggressive insulin regulation may interrupt lamellar inflammation before irreversible damage occurs, given the documented inflammatory signaling at the onset of Obel grade 1
- •The modest inflammatory profile in EMSAL compared to sepsis-associated laminitis suggests metabolic laminitis may have a longer therapeutic window and could respond to targeted interventions addressing STAT pathway activation
Key Findings
- •Lamellar mRNA concentrations of IL-1β, IL-6, IL-11, COX-2, and E-selectin were significantly increased in the euglycemic-hyperinsulinemic clamp group compared to controls
- •Phosphorylated STAT1 and STAT3 proteins were significantly elevated in the hyperinsulinemic group, with P-STAT3 localizing to lamellar basal epithelial cell nuclei
- •Unlike sepsis-associated laminitis, EMSAL showed modest inflammatory signaling without notable leukocyte infiltration into lamellar tissue
- •COX-1 mRNA concentration was decreased while COX-2 was increased, suggesting altered prostaglandin metabolism in hyperinsulinemic laminitis