Raised interleukin 31 transcription in a canine model of acute atopic dermatitis does not correlate with T cell infiltration

Interleukin 31 (IL-31) has been identified as an important cytokine in the pathophysiology of atopic dermatitis (AD) in both humans and dogs, and is a key mediator in the pruritus and TH2-weighted inflammation which characterizes this allergic condition.1 IL-31 is produced predominantly by activated T cells and memory T cells, preferentially TH2, and also by mast cells, eosinophils, basophils, macrophages and dendritic cells.1,2 However the origin of IL-31 in the skin is unclear: one study identified IL-31 transcription in infiltrating cells, presumed to be T cells, but another study associated IL-31 protein immunostaining with CD11b+ or CD11c+ cells in the skin, but not CD3+ T cells.3,4
IL-31 is thought to have diverse functions in the skin including regulation of keratinocyte differentiation and filaggrin expression, promoting interaction between keratinocytes and eosinophils, eosinophil chemotaxis, promoting nerve growth and stimulating secretion of proinflammatory cytokines, chemokines, and matrix metalloproteinase by keratinocytes and dendritic cells.5-11 In addition, IL-31 has been shown to directly activate sensory neurons in the skin, providing a critical link between cells of the immune and nervous systems in communicating the sensation of pruritus associated with allergic skin disease.12
Over the last 20 years, numerous studies have established the striking similarities between human (AD) and canine atopic dermatitis (cAD), leading to the proposition that cAD can be used as a relevant model for humans.13-15 Naturally occurring cAD is very common in dogs, and its epidemiology, clinical presentation, diagnosis and pathophysiology appear to closely parallel that of AD in human patients, with the exception that dogs very rarely develop allergic asthma and rhinitis.13-15 As in humans, the hallmarks of cAD are epidermal barrier defects and aberrant T helper type 2 (TH2)-weighted immune responses to environmental allergens.13-15 Likewise, 80% of affected dogs have classical cAD, with allergen-specific IgE, while 20% have cAD-like disease which is clinically indistinguishable but presents without detectable allergen-specific IgE.13 Concomitant food allergies, dysbiosis of the skin microbiome and secondary Staphylococcal infection are also common in dogs.13,16 The management and treatment of cAD is also similar human AD, with the addition of allergen-specific immunotherapy, Janus Kinase (JAK) inhibitors and anti-IL-31 therapeutic monoclonal antibody being in general use for cAD.13-15 The development and adoption of novel treatments for cAD, such as JAK inhibitors and anti-IL-31 monoclonals, is often accelerated by the reduced expense of clinical trials and lower regulatory requirements in veterinary medicine.13,15
Levels of IL-31 in the serum of atopic dogs has been found to correlate with the severity of clinical signs, and transcription of IL-31 mRNA has been shown to be increased in peripheral blood mononuclear cells from atopic dogs.17-19 Early studies failed to demonstrate IL-31 transcription in canine skin, however Olivry et al demonstrated increased IL-31 mRNA in lesional skin from an experimental canine model of acute house dust mite-induced AD. 20,21 A recent study of IL-31 transcription in canine skin demonstrated very low levels of IL-31 transcription in both healthy and atopic dogs using in-situ hybridization, but this study did not examine which cells in the skin were responsible or changes during inflammation.22
The objectives of our studies were to identify transcription of IL-31 in normal and atopic canine skin, to examine how transcription is affected during allergic inflammation, and to examine whether transcription of IL-31 correlates with changes in eosinophils and CD3+ T cells in the skin of atopic dogs over the course of an acute inflammatory response.