IL‐31 transgenic mice show reduced allergen‐induced lung inflammation

Abstract

Interleukin‐31 (IL‐31) is a Th2 cell–derived cytokine that has been closely linked to pruritic skin inflammation. More recently, enhanced IL‐31 serum levels have also been observed in patients with allergic rhinitis and allergic asthma. Therefore, the main aim of this study was to unravel the contribution of IL‐31 to allergen‐induced lung inflammation. We analyzed lung inflammation in response to the timothy grass (Phleum pratense) pollen allergen Phl p 5 in C57BL/6 wild‐type (wt) mice, IL‐31 transgenic (IL‐31tg) mice, and IL‐31 receptor alpha‐deficient animals (IL‐31RA−/−). IL‐31 and IL‐31RA levels were monitored by qRT‐PCR. Cellular infiltrate in bronchoalveolar lavage fluid (BALF) and lung tissue inflammation, mucus production as well as epithelial thickness were measured by flow cytometry and histomorphology. While allergen challenge induced IL‐31RA expression in lung tissue of wt and IL‐31tg mice, high IL‐31 expression was exclusively observed in lung tissue of IL‐31tg mice. Upon Phl p 5 challenge, IL‐31tg mice showed reduced numbers of leukocytes and eosinophils in BALF and lung tissue as well as diminished mucin expression and less pronounced epithelial thickening compared to IL‐31RA−/− or wt animals. These findings suggest that the IL‐31/IL‐31RA axis may regulate local, allergen‐induced inflammation in the lungs.

Interleukin‐31: The “itchy” cytokine in inflammation and therapy

“…6,7,112 In addition, IL-31 receptor IL31RA was found enhanced in lung tissue from mouse models of airway hyperresponsiveness, ovalbumin-induced asthma, and allergen-induced lung inflammation. 1,113,114 Elevated IL-31 levels have previously been reported in patients with allergic rhinitis (AR). And IL-31 triggered the production of IL-4, IL-5, and IL-13 from PBMCs and nasal epithelial cells from AR patients.…”

“…113,114 Additionally, Il31Tg mice demonstrate reduced allergen-induced inflammation in the lungs. 118 It has been suggested that this is due to the ability of IL31RA signaling to suppress the proliferation of CD4 + T cells, which in turn leads to a decreased production of T H 2 cytokines. In mice, the IL31/IL31RA axis might therefore play a dual role in asthma and allergic lung inflammation with an early pro-inflammatory and a late anti-inflammatory response or negative feedback loop.…”

IL-31 uncouples skin inflammation from itch sensation in allergic dermatitis

“…The copyright holder for this preprint (which this version posted May 13, 2021. ; https://doi.org/10.1101/2021.05.12.443916 doi: bioRxiv preprint 4 gut in Il31ra-deficient mouse strains, indicating that IL-31 can function as a negative regulator of type 2 inflammation (7)(8)(9). There are multiple potential explanations for these seeminglydiscordant results.…”

“…In IL31Tg animals, however, the contributions of IL-31 to tissue inflammation are difficult to discern because effects of IL-31 on cutaneous immune cells and keratinocytes cannot be dissociated from secondary effects of scratching-induced skin injury. In fact, enhanced rather than diminished type 2 inflammatory responses were observed in lung and gut in Il31ra-deficient mouse strains, indicating that IL-31 can function as a negative regulator of type 2 inflammation (7)(8)(9). There are multiple potential explanations for these seeminglydiscordant results.…”

“…There are multiple potential explanations for these seeminglydiscordant results. First, IL31Tg skin and Il31ra-deficient lung and gut phenotypes may reflect physiological differences specific to each organ (9); without scratching-induced skin injury as a confounder, Il31ra-deficiency may unmask inhibitory effects of IL-31 on tissue inflammation. It has also been suggested that amplified type 2 inflammatory phenotypes observed in Il31radeficient animals may occur as a consequence of liberating its binding partner, OSMRb, and thus enhancing signaling via OSMRb's other ligands (10).…”