Eosinophil-derived leukotriene C4 signals via type 2 cysteinyl leukotriene receptor to promote skin fibrosis in a mouse model of atopic dermatitis

Abstract

Atopic dermatitis (AD) skin lesions exhibit epidermal and dermal thickening, eosinophil infiltration, and increased levels of the cysteinyl leukotriene (cys-LT) leukotriene C 4 (LTC 4 ). Epicutaneous sensitization with ovalbumin of WT mice but not ΔdblGATA mice, the latter of which lack eosinophils, caused skin thickening, collagen deposition, and increased mRNA expression of the cys-LT generating enzyme LTC 4 synthase (LTC 4 S). Skin thickening and collagen deposition were significantly reduced in ovalbumin-sensitized skin of LTC 4 S-deficient and type 2 cys-LT receptor (CysLT 2 R)-deficient mice but not type 1 cys-LT receptor (CysLT 1 R)-deficient mice. Adoptive transfer of bone marrow-derived eosinophils from WT but not LTC 4 S-deficient mice restored skin thickening and collagen deposition in epicutaneous-sensitized skin of ΔdblGATA recipients. LTC 4 stimulation caused increased collagen synthesis by human skin fibroblasts, which was blocked by CysLT 2 R antagonism but not CysLT 1 R antagonism. Furthermore, LTC 4 stimulated skin fibroblasts to secrete factors that elicit keratinocyte proliferation. These findings establish a role for eosinophil-derived cys-LTs and the CysLT 2 R in the hyperkeratosis and fibrosis of allergic skin inflammation. Strategies that block eosinophil infiltration, cys-LT production, or the CysLT 2 R might be useful in the treatment of AD.murine model of atopic dermatitis | eicosanoid S kin thickening with hyperkeratosis and increased type I collagen deposition is an important feature of chronic atopic dermatitis (AD) (1). Eosinophil infiltration of target tissues is an important feature of allergic diseases, including AD. Tissue eosinophilia has long been associated with fibrosis because eosinophils and their derived products are commonly present in inflammatory fibrotic lesions (2). In addition to the release of cytotoxic granule proteins, which include major basic protein and eosinophil cationic protein, eosinophils secrete an array of inflammatory and fibrogenic mediators, including lipid mediators, chemokines, and cytokines (3). Accumulating evidence has suggested a potential role for eosinophils in airway remodeling in asthma. Genetic ablation of eosinophils, or reduction of pulmonary eosinophilia by targeting IL-5, significantly reduces subepithelial deposition of ECM proteins in a mouse model of chronic pulmonary inflammation (4). In mild asthmatics treated with anti-IL-5, reduction of infiltrating numbers of eosinophils in the bronchial mucosa was associated with a significant decrease in the expression of ECM proteins (5).Cysteinyl leukotrienes (cys-LTs) include leukotriene C 4 (LTC 4 ), which is synthesized by a variety of cells and enzymatically converted into leukotriene D 4 and then leukotriene E 4 by cleavage of its peptide side chain. LTC 4 is formed by LTC 4 synthase (LTC 4 S) through the conjugation of glutathione to the unstable intermediate leukotriene A 4 (LTA 4 ) which is generated by the action of 5-lipoxygenase (5-LO) on released arachidonic acid in the presenc...

Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation

“…local eosinophil-derived cys-leukotrienes induce fibrotic changes in a mouse model of atopic dermatitis after allergen challenge highlights the potential importance of such a mechanism even beyond of the lung (17).…”

Leukotrienes orchestrating allergic skin inflammation

“…Intriguingly, at the same time, CysLT 2 R on DCs, conversely, counteracted allergic pulmonary inflammation (55), indicating an intricate regulatory network constituted by cys-LTs and their receptors controlling DC activity. In allergic skin inflammation to OVA, on the other hand, cys-LTs were not critical for sensitization (43). At this point, it remains elusive if these distinct roles of cys-LTs in allergic pulmonary and allergic skin inflammation reflect organ-specific or rather allergen-specific differences of the mechanisms in the sensitization phase of T H 2 allergies.…”

“…Likewise, the role of LTC 4 in AD has recently been addressed by means of the epicutaneous sensitization model (43). In contrast to LTB 4 , LTC 4 was not required to direct immune cell recruitment into the skin, but was a major regulator of skin structure alterations, precisely skin thickening and collagen deposition resulting in dermal papillary fibrosis and epidermal hyperplasia (Fig.…”

The role of leukotrienes in allergic diseases

“…195 A recent study showed that eosinophil-derived LTC 4 and CysLT 2 are critical for promoting skin fibrosis and increased collagen deposition in a mouse model of AD. 196 More studies are needed to clarify the precise role of CysLTs in the pathogenesis of AD.…”

“…Atopic dermatitis 196 skin fibrosis collagen deposition Eye Allergic conjuntivitis 197 mucin secretion by goblet cells Systemic disorder Anaphylaxix 170, 200e202 mast cell activation vascular permeability between contractile mediators, such as CysLTs and histamine, 164 and vasodilators, such as prostaglandin E 2 . 165 CysLTs increase the production of certain cytokines and vice versa.…”