IL‐31 and IL‐31 receptor expression in acute experimental canine atopic dermatitis skin lesions

Abstract

Background -To optimise the interleukin (IL)-31-blocking therapy in atopic dermatitis (AD), an understanding of the chronology in the expression of IL-31 and its receptor (IL-31RA) is needed.Hypothesis/Objectives -(i) To assess the chronological expression of IL-31 in canine AD skin lesions, (ii) to compare it with serum IL-31 levels and macroscopic skin lesion scores, and (iii) to determine the identity of IL-31and IL-31RA-positive cells.Animals -Four atopic dogs sensitised to house dust mites.Methods and materials -Skin and blood samples were obtained 0 h, 24 h, 48 and 96 h after allergen provocation. IL-31 and IL-31RA single-staining immunofluorescence (IF), as well as IL-31/CD3, IL-31/CD4 and IL-31RA/ b3-tubulin double-staining IF were performed. The IL-31-positive cells were counted subjectively.Results -The peak IL-31 expression for three of four dogs occurred 24 h or 48 h postchallenge; it started to decrease at 96 h. There was no significant correlation between the IL-31 expression scores and the serum IL-31 concentrations or the macroscopic skin lesion scores (P = 0.35 and P = 0.36, respectively). The majority of IL-31positive cells were positive for CD3 (range 91-100%) and CD4 (range 63-100%), indicating that they were helper T (Th) cells. Unexpectedly, sebaceous glands were strongly immunolabelled with IL-31; the extinction of this positivity after immunoabsorption with IL-31 further supported the validity of this immunostaining. The IL-31RA was visualised on keratinocytes and a small proportion of dermal nerves.Conclusions and clinical importance -The early and transient production of IL-31 by Th cells supports the concept of using IL-31 inhibiting strategies as a proactive therapy to prevent flares of AD skin lesions.

Cytokine transcriptome profiling in acute experimental canine atopic dermatitis skin lesions after IL‐31 inhibition with lokivetmab

“…In agreement with our previous study results, 17 we did not observe any significant difference in macroscopic and microscopic skin lesion scores between the LKV and NTC groups at any sampling time points, even though the presence of LKV in the systemic circulation was confirmed by high LKV titres in the LKV-treated group during the entire study period. Our findings further support the proposition that IL-31 is not essential for the induction of acute allergic skin inflammation, which could explain why proactive therapy with LKV is insufficient to prevent AD flares in some dogs.…”

“…13 Furthermore, using the same model, we failed to detect a correlation between the severity of macroscopic inflammatory skin lesions and the amount of infiltrating IL-31-positive cells, further supporting the minimal role of locally released IL-31 in the development of acute flares of allergic skin inflammation. 17 Finally, in our prospective clinical study enrolling client-owned dogs with AD, we observed that half of the dogs treated proactively with LKV monotherapy eventually needed additional anti-allergic medications after two months, indicating other inflammatory mediators, besides IL-31, contribute to flares of AD. 13 The objectives of this study were first to compare the comprehensive transcriptome analysis of a group of dogs treated with LKV (LKV group) with an untreated group of dogs (nontreatment control group: NTC group) to attest our hypothesis that LKV does not majorly affect other cytokine/chemokine production.…”

Cannabinoid receptors in the inflammatory cells of canine atopic dermatitis

“…To identify T -cells, the dog-specific anti-cluster of differentiation 3 (CD3) antibody was used ( 57 ). A recent study has shown that canine CD3 might also be expressed by Th2 cells ( 26 ) which play a pivotal role in AD pathogenesis.…”

“…In AD-related hypersensitivity a Th2-polarized lymphocyte response is activated by keratinocytes which produce cytokines (Interleukin [IL]-25 and IL-33), and thymic stromal lymphopoietin (TSLP) which leads to Th2 immune deviation ( 1 , 8 , 18 , 19 ). Activated Th2 cells release IL-31 which stimulate itching by acting on IL-31 receptor A (IL-31RA) expressed on sensory nerve fibers and various immune cells, such as MCs, macrophages, DCs, eosinophils and basophils ( 20 – 26 ). Macrophages are also stimulated by inflammatory cytokines secreted by keratinocytes, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-α), IL-6 and IL-2 ( 17 , 27 – 29 ).…”

Allergen sensitization stratifies IL-31 production by memory T cells in atopic dermatitis patients

“…Aeroallergens such as house dust mite (HDM) are associated to disease severity and total IgE levels in AD ( 32 , 33 ). The relationship between IL-31 and allergens has been poorly characterized and mainly limited to canine models: HDM-sensitized dogs showed IL-31 expression in CD3 + CD4 + T cells in the skin lesions and production of IL-31 by Th2-polarized peripheral blood mononuclear cells (PBMC) stimulated with HDM ( 7 , 34 ). Non-lesional skin from AD patients challenged with HDM induced IL-31 mRNA expression in three out of six HDM allergic patients ( 21 ).…”