Continuous activation of the IL-17F driven inflammatory pathway in acute and chronic digital dermatitis lesions in dairy cattle

Objectives of the present study were to get a deeper insight into the course of the inflammatory pathways of digital dermatitis lesions in dairy cattle by investigating the gene expression patterns throughout the different clinical stages (M0 to M4.1) of the disease. Normal skin samples (M0) were used as a reference for comparing the gene expression levels in the other M-stages through RNA Seq-technology. Principal component analysis revealed a distinct gene expression pattern associated with digital dermatitis lesions in comparison to healthy skin with a further clustering of the acute M1, M2 and M4.1 stages versus the chronic M3 and M4 stages. The majority of the up-and downregulated genes in the acute and chronic stages can be placed into a common 'core' set of genes involved in inflammation, such as A2ML1, PI3, CCL11 and elafin-like protein, whereas the most downregulated genes included keratins and anti-inflammatory molecules such as SCGB1D and MGC151921. Pathway analysis indicated the activation of the pro-inflammatory IL-17 signaling pathway in all the M stages through the upregulation of IL-17F. These results indicate that digital dermatitis is associated with an excessive inflammatory immune response concomitant with a disrupted skin barrier and impaired wound repair mechanism. Importantly, despite their macroscopically healed appearance, a significant inflammatory response (Padj < 0.05) was still measurable in the M3 and M4 lesions, potentially explaining the frequent re-activation of such lesions