IL-18 is a key proximal mediator of contact hypersensitivity and allergen-induced Langerhans cell migration in murine epidermis

Abstract

Langerhans cells (LC) migrate rapidly from epidermis to lymph node following epicutaneous application of antigen. In this study, we have explored the role of IL-18, a cytokine with structural similarities to IL-1 beta, in murine LC migration and contact hypersensitivity (CHS), which to oxazolone (OX) and 2-4,dinitrofluorobenzene (DNFB) was suppressed significantly in IL-18 knockout (IL-18-/-) mice and could be rescued by local intradermal administration of IL-18 prior to sensitization, suggesting that the defect in these mice was in the afferent phase of CHS. To determine the effect of IL-18 on LC migration, mice were treated topically with OX or DNFB, and remaining LC numbers were assessed. A significant decline in remaining epidermal LC occurred in wild-type (WT) mice but did not occur in IL-18-/- mice. Sodium lauryl sulfate, a nonantigenic LC migratory stimulus, induced equivalent LC migration in IL-18-/- and WT mice. In IL-18-/- mice, IL-1 beta and TNF-alpha were equally able to mobilize LC from epidermis, indicating that migration in response to these cytokines is not dependent on IL-18 and suggesting that IL-18 acts upstream of these cytokines in the initiation of antigen-induced LC migration. Moreover, IL-1 beta but not IL-18 was able to rescue the defective CHS response observed in caspase-1-/- mice, which have no functional IL-1 beta or IL-18. These data indicate that IL-18 is a key proximal mediator of LC migration and CHS, acting upstream of IL-1 beta and TNF-alpha, and may play a central role in regulation of cutaneous immune responses.

The Adverse Outcome Pathway for Skin Sensitisation Initiated by Covalent Binding to Proteins

“…CCL19, CCL21) and epidermal cytokines (e.g. interleukin (IL), IL-1 α, IL-1β, IL-18, tumour necrosis factor alpha (TNF-α)) maturing dendritic cells migrate from the epidermis to the dermis of the skin and then to the proximal lymph nodes, where they can present the hapten-protein complex to T-cells via a major histocompatibility complex molecule (Antonopoulos et al, 2008;Ouwehand et al, 2008). Dendritic cell activation, upon exposure to sensitizers, also leads to functional changes in the cells.…”

In Vitro Approaches for Detection of Chemical Sensitization

“…In skin sensitization, cells are stressed to release adenosine triphosphate (ATP) leading to NLRP3 inflammasome activation, and processing and secretion of IL-1b, IL-18 and IL-33, among others. Especially, IL-18 is consistently found to play a central role in skin sensitization induction, but not irritant contact dermatitis [28]. Respiratory exposure causes the release of ATP leading to uric acid production, activation of the NLRP3 inflammasome complex, processing and secretion of IL-1b, release of IL-6 and chemokines and enhanced differentiation of a specific IL-17-producing T-cell subpopulation (Th17) [29].…”

“…Test chemicals that exclusively react with lysine should therefore be considered outside the chemical applicability domain [31,32] Assessing IL-18 levels: IL-18 plays a proximal role in skin sensitization induction, but not in irritant contact dermatitis or asthma, by enhancing the secretion of pro-inflammatory mediators and by favouring Th-1 type immune response [28,29]. The NCTC 2544 IL-18 test was shown to be potentially useful for identification of skin sensitizers.…”

Imunopatologia da dermatite de contato alérgica

“…65 These cytokines also induce maturation and migration of LC. 66 During the process of maturation, DC increase the expression of costimulatory molecules such as CD40, CD80 and CD86, adhesion molecules such as ICAM-1 and cytokines such as IL-12. [67][68][69] The maturation process is necessary for activation of naive hapten-specific T cells in regional lymph nodes for effector and memory TL.…”