Researchers shine spotlight on damaging inflammation in laminitis

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Production of a cytokine that promotes inflammation is increased in cases of supporting limb laminitis in horses, researchers report, a finding that could open the door to therapeutic interventions.

The study by Lynne Cassimeris, Julie Engiles and Hannah Galantino-Homer focused on the proinflammatory Interleukin-17A (IL-17A) pathway.

Cytokines are secreted by specific cells of the immune system. They are signaling molecules that mediate and regulate immunity and inflammation, among other roles.

Supporting limb laminitis is a painful and crippling secondary complication of orthopedic injuries and infections in horses, often resulting in euthanasia.

Activation of the IL-17A-dependent inflammatory pathway is typically an epidermal stress response that contributes to physiologic cutaneous wound healing as well as pathological skin conditions.

For their study, the researchers tested the hypothesis that, in standing limb laminitis, the equine lamellae respond to stress by expression of genes upregulated by IL-17A, in a similar reaction to that found in human skin diseases or wound healing.

The authors used archived lamellar tissue isolated from Thoroughbreds euthanized following naturally occurring standing limb laminitis to compare with tissue samples from horses without laminitis.

Schematic overview of equine hoof lamellar tissue anatomy.
Schematic overview of equine hoof lamellar tissue anatomy. Left panel: cutaway view of the midsagittal section of an equine foot outlining the position of lamellar tissue (red) relative to hoof wall (grey) and distal phalanx (DP), middle phalanx, and distal sesamoid bones (blue). The transverse section plane used for tissue collection is shown in yellow. Center panel: a portion of the transverse section plane diagrammed schematically. The interdigitating primary epidermal lamellae (PEL) and primary dermal lamellae (PDL) are highlighted. Right panel: higher magnification illustration of lamellar tissue organization.

IL-17A was primarily detectable only in laminitic tissue samples, with the target genes behind the IL-17A pathway strongly upregulated when compared to the non-laminitic tissue.

The authors noted that equine laminitis shares several similar features to psoriasis in humans, with the IL-17A pathway having a role in the progression of the skin disease.

“Assuming IL-17A pathway activation contributes to disease progression in equine laminitis, as it does in human skin diseases, blocking this pathway could lead to development of a therapeutic treatment amenable to use in horses,” the trio reported in the journal PLOS ONE.

The researchers said inhibiting IL-17A signaling in the horse will not be as simple as applying human therapies since the most successful psoriasis treatments use monoclonal antibodies to block IL-17A receptor activation.

“These antibodies may not bind the equine IL-17A receptor, may be antigenic in equines, and are likely cost-prohibitive.”

However, local inhibition of IL-17A in affected tissue, possibly using an adeno-associated viral vector to deliver genes able to inhibit IL-17A-dependent signals, or to express inhibitory cytokines to block inflammation, could be promising once it is established that the IL-17A pathway contributes to laminitis progression.

In conclusion, they said their findings show upregulation of a group of IL-17A target genes in cases of supporting limb laminitis in horses. The findings also support the hypothesis that similarities in the response to stresses and damage exist between equine and human epidermal tissues.

Cassimeris is with the Department of Biological Sciences at Lehigh University in Pennsylvania; and Engiles and Galantino-Homer are with the New Bolton Center, part of the School of Veterinary Medicine at the University of Pennsylvania.

Cassimeris L, Engiles JB, Galantino-Homer H (2020) Interleukin-17A pathway target genes are upregulated in Equus caballus supporting limb laminitis. PLoS ONE 15(12): e0232920.

The study, published under a Creative Commons License, can be read here

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