Continuous digital hypothermia reduces expression of keratin 17 and 1L-17A inflammatory pathway mediators in equine laminitis induced by hyperinsulinemia.
Authors: L. Cassimeris, Caitlin Armstrong, Quinnlyn C Burger, S. Stokes, A. V. van Eps, H. Galantino-Homer
Journal: Veterinary immunology and immunopathology
Summary
Endocrinopathic laminitis triggered by hyperinsulinaemia causes rapid deterioration of lamellar tissue through keratinocyte dysfunction and inflammation, yet the precise molecular mechanisms remain incompletely understood. Researchers used archived lamellar tissue from eight horses subjected to a 48-hour euglycemic hyperinsulinaemic clamp (EHC) model—with continuous digital hypothermia (CDH) applied to front limbs only—to identify which genes and inflammatory pathways CDH could suppress, thereby revealing those critical to disease initiation. Cooling significantly reduced expression of eight inflammatory mediators including keratin 17 (KRT17), chemokines (CCL2, CXCL8), cyclooxygenase-2 (PTGS2/COX2), and the cytokines IL-6 and TNF-α, whilst genes such as IL-17A, DEFB4B, S100A9 and MMP9 showed no significant reduction in cooled tissue. Immunofluorescence confirmed that COX2 protein was robustly expressed in keratinocytes from normothermic limbs but virtually absent in CDH-treated tissue, establishing keratinocytes themselves—rather than infiltrating immune cells—as key drivers of the early inflammatory cascade. These findings suggest that therapeutic cooling interrupts keratinocyte stress-activation pathways, offering evidence-based rationale for continued use of cryotherapy in acute laminitis management and identifying potential molecular targets for adjunctive anti-inflammatory intervention.
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Practical Takeaways
- •Continuous digital hypothermia effectively suppresses multiple inflammatory pathways in hyperinsulinemic laminitis, particularly keratinocyte-mediated inflammation, supporting its use as a therapeutic intervention during acute episodes
- •Keratinocytes are key drivers of lamellar inflammation in endocrinopathic laminitis; therapeutic strategies targeting keratinocyte stress responses may offer benefit beyond cooling alone
- •Some inflammatory mediators (IL-17A, MMP9) are not suppressed by cooling, suggesting they may operate through alternative pathways and could be targets for complementary treatments
Key Findings
- •Continuous digital hypothermia (CDH) significantly reduced expression of 8 of 12 inflammatory genes measured in laminitic lamellar tissue, including KRT17, CCL2, CXCL8, PTGS2, IL6, TNFα, S100A8, and MMP1
- •COX2 protein was robustly expressed in lamellar keratinocytes from limbs at ambient temperature but absent in CDH-treated limbs
- •IL-17A, DEFB4B, S100A9, and MMP9 expression were not significantly reduced by CDH treatment
- •Keratinocytes appear to play a central role in equine laminitis pathogenesis through stress-induced inflammatory pathways