IL-36α is involved in hapten-specific T-cell induction, but not local inflammation, during contact hypersensitivity

Highlights

• IL-36α was detected in the skin of psoriatic dermatitis, but not contact dermatitis.

• IL-36α is not essential for dendritic cell migration.

• IL-36α is involved in hapten-specific T-cell induction and activation.

• IL-36α is not essential for induction of the inflammation of contact dermatitis.

Abstract

Levels of IL36α are known to be increased in specimens from patients with atopic dermatitis and psoriasis. In addition, it has been reported that IL-36α is crucial for development of imiquimod-induced psoriatic dermatitis in mice. On the other hand, the role of IL-36α in induction of allergic contact dermatitis/contact hypersensitivity (ACD/CHS) is poorly understood. We found that IL-36α was produced in keratinocytes of mice during imiquimod-induced psoriatic dermatitis, but it was hardly detectable in the skin of mice during either fluorescein isothiocyanate (FITC)- or 1-fluoro-2, 4-dinitrobenzene (DNFB)-induced CHS. Although IL-36α can enhance activation of dendritic cells (DCs) and T cells, in CHS, IL-36α was not essential for DC migration from the skin to draining LNs, but it was required for induction or activation of hapten-specific T cells such as Th/Tc1 or Th17 cells. However, local inflammation, assessed by measurement of ear skin thickness, was comparable between wild-type and IL-36α-deficient mice during both FITC- and DNFB-induced CHS. These observations indicate that IL-36α is involved in induction and/or activation of hapten-specific T-cell subsets in the sensitization phase of CHS, but not essential for induction of local inflammation in the elicitation phase.

Introduction

Allergic contact dermatitis/contact hypersensitivity (ACD/CHS), which develops in response to repeated epicutaneous exposure to a hapten [1], is a hapten-specific T-cell-mediated disease. Haptens, which are generally non-immunogenic low-molecular-weight chemicals, are capable of crossing the stratum corneum barrier and forming chemically-modified immunogenic neo-antigens by binding with self-proteins [2]. In the sensitization phase of CHS, haptenized self-proteins are captured by cutaneous dendritic cells (DCs), which then migrate to draining lymph nodes (LNs) and present the haptenized self-proteins to naïve T cells [3,4]. The naïve T cells subsequently differentiate into hapten-specific effector and memory T cells. In the elicitation phase, hapten-specific T cells in LNs are activated by DCs when re-exposed to the same haptenized self-proteins and then migrate from the LNs to the skin, resulting in induction of local inflammation.

IL-36, which is a member of the IL-1 family of cytokines, consists of three agonists, i.e., IL-36α, IL-36β and IL-36γ (formerly known as IL-1F6, IL-1F8 and IL-1F9, respectively), and an antagonist, i.e., IL-36 receptor antagonist (IL-36RN or IL-36Ra, formerly known as IL-1F5). Those four ligands are produced from distinct genes and bind to the same receptors, consisting of IL-1 receptor like 2 (IL-1RL2; also called IL-1Rrp2) and IL-1R accessory protein (IL-1RAcP; also called IL-1RAP) [5]. IL-36 is expressed in various tissues such as the skin, LNs, tonsils, bone-marrow and/or spleen, in humans and/or mice [5,6]. In addition, IL-36 is constitutively expressed and/or induced in response to certain stimuli in human and/or mouse keratinocytes, epithelial cells, endothelial cells, monocytes/macrophages, DCs and/or T cells [[7], [8], [9]]. IL-1RL2 is expressed in various tissues such as the skin, trachea, kidney, liver and thyroid, and in various types of cells such as CD4⁺ T cells, macrophages, dendritic cells (DCs), neutrophils and keratinocytes [8,10]. It has been shown that IL-36 can enhance T-cell proliferation, promote Th1 and Th17 immune responses [8,11,12] and induce IFN-γ production in combination with IL-2 and IL-12 on CD8⁺ T cells [13]. On the other hand, excessive/inappropriate production of IL-36 may contribute to development of certain chronic inflammatory diseases such as rheumatoid arthritis [14], Sjögren's syndrome [15] and inflammatory bowel diseases [16].

In regard to skin diseases in humans, expression of IL-36 is increased in specimens from patients with ACD/CHS [17,18], atopic dermatitis (AD) [19] and psoriasis [[20], [21], [22]], suggesting that these cytokines may be involved in development of such skin diseases. Indeed, it has been reported that development of imiquimod-induced dermatitis, which is considered to be a model of psoriasis, was impaired in IL-36α-deficient (Il36a^−/−) and Il1rl2^−/− mice, but not Il36b^−/− or Il36g^−/− mice [[23], [24], [25]], indicating that IL-36α, but not IL-36β or IL-36γ, is crucial for that development. On the other hand, little is understood regarding whether IL-36 is involved in the pathogenesis of ACD/CHS. Here, we investigated that issue using Il36a^−/− mice and found that IL-36α is required for induction of hapten-specific T cells, but not induction of the local inflammation of ACD/CHS in mice.