Acta Dermato-Venereologica issue 50:1 98-1CompleteContent | Page 9

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REVIEW ARTICLE
Highlighting Interleukin-36 Signalling in Plaque Psoriasis and
Pustular Psoriasis
Kazuhisa FURUE 1 , Kazuhiko YAMAMURA 1 , Gaku TSUJI 1 , Chikage MITOMA 1,2 , Hiroshi UCHI 1 , Takeshi NAKAHARA 1,3 , Makiko
KIDO-NAKAHARA 1 , Takafumi KADONO 4 and Masutaka FURUE 1–3
Department of Dermatology, 2 Division of Skin Surface Sensing, Department of Dermatology, Kyushu University, 3 Research and Clinical Center
for Yusho and Dioxin, Kyushu University Hospital, Kyushu University, Fukuoka, and 4 Department of Dermatology, St Marianna University
School of Medicine, Kanagawa, Japan
1
Plaque psoriasis and pustular psoriasis are overlap-
ping, but distinct, disorders. The therapeutic response
to biologics supports the pivotal role of the tumour ne-
crosis alpha (TNF-α)/ interleukin (IL)-23/IL-17/IL-22
axis in the pathogenesis of these disorders. Recently,
functional activation of the IL-36 receptor (IL-36R)
was discovered to be another driving force in the pat-
hogenesis of psoriasis. This was first highlighted by
the discovery that a loss-of-function mutation of the
IL-36R antagonist (IL-36Ra) causes pustular psoria-
sis. Although the TNF-α/IL-23/IL-17/IL-22 axis and
the functional activation of IL-36R are fundamentally
involved in plaque psoriasis and pustular psoriasis,
respectively, the 2 pathways are closely related and
mutually reinforced, resulting in full-blown clinical
manifestations. This review summarizes current topics
on how IL-36 agonists (IL-36α, IL-36β, IL-36γ) signal
IL-36R, the pathological expression of IL-36 agonists
and IL-36Ra in plaque and pustular psoriatic lesions,
and the cross-talk between the TNF-α/IL-23/IL-17/
IL-22 axis and the functional activation of IL-36R in
the epidermal milieu.
Key words: psoriasis; pustular psoriasis; IL-36; IL-36 receptor;
IL-36 receptor antagonist; IL-17; IL-22.
Accepted Oct 2, 2017; Epub ahead of print Oct 2, 2017
Acta Derm Venereol 2018; 98: 5–13.
Corr: Masutaka Furue, Department of Dermatology, Kyushu University,
Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582, Japan. E-mail: furue@
dermatol.med.kyushu-u.ac.jp
P
soriasis is a common, immune-mediated, chronic
inflammatory, erythemato-desquamative skin di-
sease that is characterized by the altered proliferation
and differentiation of keratinocytes with infiltration of
neutrophils, dendritic cells (DCs) and T cells (1, 2). Pso-
riasis has shown a diverse prevalence across populations
worldwide: 2.5% in Europeans, 0.05–3% in Africans
and 0.1–0.5% in Asians (1, 2). Psoriasis is divided into 2
major clinical variants, plaque psoriasis and generalized
pustular psoriasis, with shared pathogenetic backgrounds
(1–4). Pustule formation of plaque psoriasis is not un-
common in severe cases (1, 4). A recent study revealed
that palmoplantar pustulosis, a localized variant of pustu-
lar dermatosis, shares a similar pathogenesis with the
generalized form (5). The therapeutic guidelines include
the use of topical steroids, topical vitamin D, systemic
immunosuppressants and various biologics, such as anti-
tumour necrosis factor (TNF) α, anti-interleukin (IL)-23
and anti-IL-17 antibodies (6–14). However, treatment
adherence and the quality of life of the affected patients
are generally very low (1, 15–20). Recent genome-wide
association studies have identified many susceptibility
loci for psoriasis and pustular psoriasis, including HLA-
C*06:02, LCE3D, IL23R, CARD14 and IL36RN (21–24).
These susceptibility genes are predominantly related
to the innate and adaptive immune systems and to skin
barrier functions (1, 21).
Psoriasis often coexists with other systemic diseases,
such as arthritis, diabetes mellitus, arterial hypertension,
obesity and cardiovascular diseases (the so-called “pso-
riatic march” or “inflammatory march”) (25–30). Pso-
riasis is also co-morbid with other autoimmune diseases,
including Hashimoto’s thyroiditis and autoimmune bul-
lous diseases (31–36). The recent therapeutic success
of anti-TNF-α, anti-IL-23 and anti-IL-17 antibodies, as
well as the diverse action of IL-22, has emphasized the
pivotal role of the TNF-α/IL-23/IL-17/IL-22 pathway in
the pathogenesis of plaque psoriasis and pustular pso-
riasis (2, 37, 38). In addition to the TNF-α/IL-23/IL-17/
IL-22 pathway, IL-36 and IL-36 receptor antagonist (IL-
36Ra/IL36RN) are currently the focus of much attention.
The gene and immunohistological expression of IL-36
members is upregulated in plaque psoriasis and pustular
psoriasis (39–41). Moreover, IL36RN deficiency has been
associated with the development of generalized pustular
psoriasis (23, 42). This review summarizes recent topics
on IL-36 signalling with reference to plaque psoriasis
and pustular psoriasis.
IL-36 MEMBERS AND THEIR RECEPTOR
Epithelial cells, including keratinocytes, are a good
source of the IL-1 family (IL-1F), which is composed
of 11 members: IL-1α, IL-1β, IL-1 receptor antagonist
(IL-1RN), IL-18, IL-33, IL-36α/IL-IF6, IL-36β/IL-1F8,
IL-36γ/IL-1F9, IL-36Ra/IL-1F5, IL-37/IL-1F7 and IL-
38/IL-1F10 (43–45). IL-36α, IL-36β, IL-36γ and IL-
36Ra use the same receptor, IL-36R (previously called
IL-1Rrp2 or IL-1RL2), coupled with the IL-1 receptor
accessory protein (IL1RAP), which is a common subunit
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2018 Acta Dermato-Venereologica.
doi: 10.2340/00015555-2808
Acta Derm Venereol 2018; 98: 5–13