Biochemical and Biophysical Research Communications
IL-36α is involved in hapten-specific T-cell induction, but not local inflammation, during contact hypersensitivity
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.
Section snippets
Mice
C57BL/6J-wild-type mice were obtained from Sankyo Labo Service Corporation (Tsukuba, Japan). C57BL/6J-Il36a−/− mice were generated as described previously [25]. All mice were housed in a specific-pathogen-free environment at The Institute of Medical Science, The University of Tokyo. The protocol for the animal experiments was approved by the Institutional Review Board of the Institute (A14-10), and all experiments were conducted according to the ethical and safety guidelines of the Institute.
Induction of dermatitis
IL-36α is increased in the skin during IMQ-induced psoriatic dermatitis, but not hapten-induced CHS
The expression levels of IL-36α were increased in patients with psoriasis [17,22], and keratinocyte-derived IL-36α is known to be crucial for development of IMQ-induced psoriasis-like dermatitis in mice [23,24]. First, we used qPCR and immunohistochemical analysis to compare the expression levels of IL-36α in the inflamed skin of wild-type mice and Il36a−/− mice (as negative controls) during IMQ-induced psoriasis-like dermatitis and FITC- and DNFB-induced CHS. In the wild-type mice, the qPCR
Discussion
Several lines of evidence demonstrated increased expression of IL-36 in specimens from patients with psoriasis [20,21]. In addition, IL-36α, but not IL-36β or IL-36γ, is crucial for development of IMQ-induced murine psoriatic dermatitis [[23], [24], [25]]. Compared with the role of IL-36 in psoriasis, the contribution of this cytokine to development of ACD/CHS is poorly understood. In the present study, using Il36a−/− mice, we clearly demonstrated that IL-36α is somewhat involved in induction
Conflicts of interest
The authors have no conflicts of interest to declare.
Acknowledgements
We thank the members of the Medical Research Center of Tokyo Medical University Hospital for their expert technical assistance. We also thank Lawrence W. Stiver (Quality Translation Co., Ltd.; Tokyo, Japan; [email protected]) for his critical reading of the manuscript. This work was supported by a Grant-in-Aid for Scientific Research (B) (18H02847 to SN) from Japan Society for the Promotion of Science, Japan.
References (28)
- et al.
Allergic contact dermatitis: patient diagnosis and evaluation
J. Am. Acad. Dermatol.
(2016) - et al.
The effect of haptens on protein-Carrier immunogenicity
Immunology
(2015) - et al.
The fate of a hapten - from the skin to modification of macrophage migration inhibitory factor (MIF) in lymph nodes
Sci. Rep.
(2018) - et al.
Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis
J. Invest. Dermatol.
(2013) - et al.
Regulation and function of interleukin-36 cytokines
Immunol. Rev.
(2018) - et al.
Biology of IL-36 cytokines and their role in disease
Semin. Immunol.
(2013) - et al.
New insights in the immunobiology of IL-1 family members
Front. Immunol.
(2013) - et al.
IL-36R ligands are potent regulators of dendritic and T cells
Blood
(2011) - et al.
Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation
J. Immunol.
(2013) - et al.
Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs
J. Biol. Chem.
(2004)
IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells
Blood
Staphylococcus aureus epicutaneous exposure drives skin inflammation via IL-36-mediated T cell responses
Cell Host Microbe
Costimulation endows immunotherapeutic CD8 T cells with IL-36 responsiveness during aerobic glycolysis
J. Immunol.
The novel cytokine interleukin-36α is expressed in psoriatic and rheumatoid arthritis synovium
Ann. Rheum. Dis.
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