INTERLEUKIN 25, THYMIC STROMAL LYMPHOPOIETIN AND HOUSE DUST MITES IN PATHOGENESIS OF ATOPIC DERMATITIS
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JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2020, 71, 2, 291-297
www.jpp.krakow.pl | DOI: 10.26402/jpp.2020.2.14
A.K. JAWOREK1, K. SZAFRANIEC2, Z. ZUBER3, A. WOJAS-PELC1, J. JAWOREK4
INTERLEUKIN 25, THYMIC STROMAL LYMPHOPOIETIN AND HOUSE DUST MITES
IN PATHOGENESIS OF ATOPIC DERMATITIS
Department of Dermatology, Faculty of Medicine, Jagiellonian University Medical College, Cracow, Poland; 2Department of
1
Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical
College, Cracow, Poland; 3Andrzej Frycz Modrzewski Cracow University, Cracow, Poland; 4Department of Medical Physiology,
Faculty of Health Sciences, Jagiellonian University Medical College, Cracow, Poland
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in the world. It is characterized by
recurrent eczematous skin lesions, fluctuating course and chronic pruritus. Increasing evidence suggest that AD is more
common in adults than previously thought. The disease is characterized by an impaired skin barrier, aberrant Th2-type
cytokine production and intensive pruritus. Epithelial keratinocytes constitute the first physical, chemical and
immunological barrier, classified as a part of the innate defense system. These keratinocytes secrete various factors, e.g.
alarmins such as thymic stromal lymphopoietin (TSLP) and interleukin 25 (IL-25). Serum levels of substance P (SP)
have been reported to be increased in patients with AD and correlated with itch intensity. Several previous studies
reported a positive association between AD severity and house dust mites (HDM) sensitization. The aim of the study
was to analyze IL-25, TSLP and SP concentrations in blood serum of adult patients with severe AD, depending on the
degree of allergy to HDM. There were 31 adult AD patients enrolled into the study and a control group that consisted
of 20 healthy subjects. AD was diagnosed on the basis of Hanifin and Rajka criteria. SCORing Atopic Dermatitis
(SCORAD) and visual analogue (VAS) scores were used to assess the intensity of pruritus and blood content of specific
IgE to HDM, as well as TSLP, IL-25 cytokines and SP was measured. Our study presents the evidence that IL-25 serum
concentration is increased in patients with atopic dermatitis and this cytokine plays an important role in pathogenesis of
this disease. HDM could stimulate the release of IL-25 which aggravates the disease severity. Our results corroborate
previous findings on the role of TSLP in atopic dermatitis.
K e y w o r d s : atopic dermatitis, epithelial cell-derived cytokines, interleukin-25, substance P, house dust mites, thymic stromal
lymphopoietin
INTRODUCTION Despite intensive research, a precise etiopathogenesis of AD
remains unclear. Among the numerous AD-related
Atopic dermatitis (AD; atopic eczema, AE) is a chronic and morphological and functional factors, dysfunction of skin
recurrent skin disease manifested by eczematous lesions barrier and immunological disorders were singled out as the
(acute, subacute or chronic) with a characteristic, age- main factors which, by interaction, contribute to the disease
dependent localization and intensive itching. AD is currently development. It is noteworthy that pruritus, which is a
the most common inflammatory dermatosis in the world, with fundamental symptom of AD, provokes the skin scratching,
a lifetime prevalence of up to 20% in developed countries (1). leading to the epidermal damage and aggravation of skin
The clinical manifestations of the disease vary widely: from inflammation (6-8).
mild lesions located in the hollows of the limbs to Substance P (SP) is a neuropeptide associated with
erythroderma - a generalized inflammation involving more neurogenic skin inflammation and pruritus. The role of SP in the
than 90% of the skin surface, which is reflected in the pathogenesis of AD is the subject of many reports. Elevated SP
differentiation of disease phenotypes (2). The presence of AD levels can be used as an indicator of disease activity (9, 10).
significantly impairs patients’ quality of life not only due to the In recent years, a growing body of evidence has indicated
irritating symptoms of the disease itself but also because of that the development of skin inflammation in AD patients is
several potential comorbidities (e.g. bronchial asthma, mental triggered mainly by epidermal damage resulting in epidermal
disorders, autoimmune diseases) (3). Although for years AD keratinocytes releasing alarmins, such as thymic stromal
was considered a childhood disease that patients could ‘grow lymphopoietin (TSLP), and interleukin IL-25 (11, 12). Also
out’ of, an increasing number of clinical reports indicate that HDM, domestic and storage mites can aggravate skin damage
the disease is also prevalent in the adult population (4, 5). and exacerbate lesions in AD patients, by affecting the skin both
292
directly (due to the activity of the mite cysteine proteases) and mellitus), taking immunosuppressive medications (up to 3
indirectly (due to their allergenic properties) (13). months prior to the study) and undergoing phototherapy up to 6
The aim of the study was to analyze IL-25, TSLP and SP months prior to the study.
serum concentrations in adult patients with severe AD in
comparison to the severity of HDM allergy. Sample collection and laboratory analysis
Blood samples were taken from ulnar vein between 7:00 am
MATERIALS AND METHODS and 8:00 am in a volume of 10 mL by the same nurse under the
same circumstances. Standard blood sampling protocols were
Compliance with ethical standards
followed; patients were fasting, after 30 minutes of rest. The
samples were kept for 2 hours at room temperature for a clot to
The study protocol was approved by the Bioethics form, then centrifuged at 3500 rpm for 10 minutes, frozen and
Committee of Jagiellonian University Medical College (consent stored at –80ºC until use. The serum content of TSLP, IL-25 and
no. 122.6120.117.2016). The design and procedures of the study SP was assessed using an ELISA assay (R&D System,
were carried out in accordance with the principles of the Minneapolis, MN) according to the manufacturer’s protocol.
Declaration of Helsinki. All subjects provided a written Total IgE concentration was evaluated during the routine
informed consent to participate in this study after a full diagnostic tests using ELISA method with the fluorimeter
explanation of the study had been provided. UniCAP (Pharmacia, Sweden). The values above 100 IU/mL
were considered as increased. Dust mite specific IgE (sIgE; d1:
Study sample Dermatophagoides pteronyssinus, d2: Dermatophagoides
farinae) antibodies were assessed using ELISA method with the
The group of 31 adult Caucasian patients (F/M: 16/15; fluorimeter UniCAP (Pharmacia, Sweden) according to
median age: 34 years old; range 20 – 72 years) suffering from manufacturer’s instruction. The level of IgE antibodies was
childhood-onset of extrinsic AD were qualified to the study. The classified as follows: Class I: 0.35 – 0.68 IU/mL, Class II: 0.70
control group consisted of 20 healthy Caucasian volunteers – 3.49 Iu/mL, Class III: 3.5 – 17.49 IU/mL, Class IV: 17.5 – 49.9
(F/M: 10/10; median age: 27 years old; range 23 – 72 years). A IU/mL, Class V: 50.0 – 100.0 Iu/mL, Class VI: > 100 Iu/mL.
study group participants were recruited at the Dermatology
Department of Jagiellonian University Medical College from Statistical analysis
January 2017 to May 2018. The diagnosis of AD was based on
the diagnostic criteria of Hanifin and Rajka (14). The severity of To describe the sample, standard measures of mean (SD) and
AD was assessed based on the SCORing Atopic Dermatitis median (min-max) were used, depending on the distribution of
(SCORAD) index, where score over 50 points indicates a severe the parameter. To compare the mean values of IL-25 and TLSP
form of the disease (15). All of the patients were classified as between the analyzed groups, the Student’s t-test and the
having severe AD (median SCORAD index: 61.4 points; min– ANOVA test were used; similar non-parametric methods were
max: 50.3 – 80.4 points). The worst itch during last 24 hours was applied to SP analysis. The calculations were made using the
evaluated with Visual-Analogue-Scale (WI-VAS; where 0 StatSoft STATISTICA package version 13.0. Tests of
points: no pruritus, 1 – 3: mild pruritus, 4 – 6: moderate pruritus, significance were 2-tailed with α = 0.05.
7 – 8: severe pruritus, 9 – 10: very severe pruritus) (16). The
characteristics of the study group are presented in Table 1.
The exclusion criteria of the selected subjects (patients and RESULTS
controls) included: lack of consent, age below 18 years, pregnant
and lactating females, systemic inflammatory disorders, Nearly all patients with severe AD (96.8%) were allergic to
presence of other cutaneous inflammatory disorders, HDM. Only one patient from the study group revealed O class for
cardiovascular diseases, metabolic diseases (e.g. diabetes house dust mite specific IgE (d1, d2). As much as 84% patients
Table 1. Characteristics of the atopic dermatitis (AD) patients and control group.
Parameter Patients Control
(n=31) (n=20)
Gender Male 15 (48.5) 10 (50)
n (%) Female 16 (51.5) 10 (50)
Age 34 27
median; min-max: (years) (20 – 72) (23 – 72)
SCORAD 61.4 0.0
median; min-max: (points) (50.3 – 80.4)
VAS 10 27 (87.1) 0.0
n (%) points 9 4 (12.9) 0.0
SCORAD, SCORing atopic dermatitis index; VAS, visual analogue scale.
Table 2. Distribution of atopic dermatitis patients by house dust mite specific IgE classes.
Classes 0 I II III IV V VI
d1 2 0 1 2 1 2 23
d2 1 1 1 2 1 2 23
293
Fig. 1. Serum IL-25 in adult
patients suffering from atopic
dermatitis (AD) and in control
subjects.
Fig. 2. Serum TSLP in adult
patients suffering from atopic
dermatitis (AD) and in control
subjects.
from the study group was categorized into higher sIgE classes The serum concentration of IL-25 was significantly higher in
(Class IV – VI), the majority of them was classified as Class VI the severe AD patients (average: 17.2 ± 3.0 pg/mL) than in the
(23 (74%) subjects d1, d2) (Table 2). All patients from the study control subjects (average: 15.2 ± 3 pg/mL ) (P < 0.033) (Fig. 1).
group (31/31; 100%) suffered from severe AD (SCORAD Moreover, there was a significant statistical difference (P <
median: 61.4 points; min-max: 50.3 – 80.4 points). According to 0.001) in TSLP serum level which was markedly higher in AD
the visual assessment scale of pruritus (VAS) all patients subjects (average: 80.8 ± 12.5 pg/mL ), as compared to the
experienced very intensive itching (VAS ≥ 9, 100%). The levels healthy control group (14.6 ± 4.5 pg/mL) (Fig. 2).
of total IgE antibodies were extraordinarily high in AD patients, However, there was no statistical difference in serum SP
ranging between 1030 to 58 600 IU/mL; median 10 600 IU/mL. concentration between patients with AD and controls (P =
294
Table 3. Blood level of substance P in patients with atopic dermatitis (AD) and healthy control group.
AD patients Control group
(n = 31) (n = 20)
Substance P Median Min Max Median Min Max P
(pg/ml) 170.6 107.6 749.0 163.5 107.9 191.6 0.148
Fig. 3. Serum IL-25 (average
and 95% CI) in classes of HDM
specific IgE (d1 d2) and in
control subjects.
Fig. 4. Serum TLSP (average
and 95% CI) in classes of HDM
specific IgE (d1 d2) and in
control subjects.
0.148), although 29% of patients had SP levels above the in the mean values of IL-25 concentration with the increase of
maximum SP levels revealed in the control group (Table 3). HDM d1, d2 classes (P = 0.015) (Fig. 3). Similar TSLP analysis
Analysis of IL-25 concentration in relation to HDM classes showed no differentiation of mean concentrations in HDM
showed the existence of a significant linear trend of the increase classes (Fig. 4).295
DISCUSSION suggested that mRNA and protein levels of IL-25 and its receptor
are elevated in the skin of individuals with AD, and their
AD is most frequently demonstrated among babies and expressions are higher in lesional skin compared to unchanged
children. The number of AD patients in the population of adults skin. IL-25 significantly reduced the mRNA signal of filaggrin in
is reduced, but still considerably high, amounting to about 7% a dose-dependent manner, supporting that IL-25 has a direct
(5, 17). International survey by Harrop et al. (18) revealed that effect on the skin structure. Secondary impetiginisation is a
AD was diagnosed in 2 – 17.6% of population in individual common phenomenon in AD. The effect of lipopolysaccharide
countries. The results of an extensive study by Barabarot et al. (LS) stimulation on IL-25 is well known (32).
(19) including the population of people from the USA, Japan, To the best of our knowledge, the IL-25 blood level in AD
Canada and Europe indicated a significant underestimation of patients has not been investigated yet. Herein it is demonstrated
the disease prevalence in adult population (the prevalence of for the first time that serum concentration of IL-25 in subjects
previously diagnosed and active AD ranged from 2.1% to 4.9%). with severe form of AD was significantly higher, compared to
Dysfunction of skin barrier, both in lesional and non-lesional healthy controls. Furthermore, an interesting relationship has
skin, plays a fundamental role in pathogenesis of allergic skin been found between IL-25 concentration and HDM. Notably, IL-
disease (20). The most important elements related to epidermal 25 serum concentration shows a significant positive linear tend
defect in patients with AD are: deficiencies of filaggrin and with increased HDM d1, d2 classes. It seems that this is the first
claudin-1, which are proteins vitally important for normal skin result showing that HDM could stimulate IL-25 production and
structure, reduction of acylceramides, and impairment of genes aggravate the symptoms of AD in patients with severe form of
encoding Epidermal Differentiation Complex (7). Experiments this disease.
on filaggrin-deficient mice revealed that skin permeability for Neuropeptides are important in the development of skin
allergic protein, including HDM protein, was strongly increased inflammation in AD. The skin of AD patients presents the
in these animals (21, 22). excessive density of cutaneous sensory nerve fibers in skin
The key role in allergic reactions is played by the Th2- lesions with increased SP - positive nerve fibers and amplified
mediated immune response and the processes it triggers: IgE mast-cell-nerve fibers in skin lesions (33, 34). Substance P, an
overproduction by plasma cells, activation of innate lymphomatoid endogenous neuropeptide of tachykinine family, mediates
cells 2 (ILC2), eosinophils, mast cells and basophils. These intracellular signaling, mainly through G-protein coupled
processes are accompanied by the release of Th-2 mediated receptors (35). This receptor was found on mast cells,
cytokines, such as IL-4, IL-5, IL-9 and IL-13 from the immune keratinocytes, and cutaneous nerve ending. Binding SP to its
system cells. The keratinocyte activation is a hallmark of the receptor resulted in the release of additional itch mediators (36).
development of AD in acute and chronic phases. Keratinocytes, as SP activates mast cell (MC) to release inflammatory mediators
part of the innate immune defense, contribute to the inflammatory such as leukotriene B4, prostaglandin D2, and TNF-α (37).
reactions and immune responses in AD by regulating the release of Serum levels of SP have been reported to be increased in patients
cytokines, chemokines, proteases, and bioactive lipids. Epidermal with AD and correlated with itch intensity. It is noteworthy that
keratinocytes secrete three cytokines, which are considered crucial serum SP remained elevated even after AD remission (9, 10). In
in mediating the Th2-dependent response: TSLP, IL-25 and IL-33 our study, SP serum concentrations in AD patients and healthy
(11, 23). TSLP belongs to the group of IL-7-like cytokines. It was controls were not statistically different, which could probably be
initially discovered in a mouse thymic stromal cell line supernatant related to the limited number of individuals in the study group
as a T and B cell growth factor (24) and subsequently identified in and considerable differences in SP concentration among
human tissue (25). The epidermis releases TSLP as a result of individual patients. Nevertheless, in about 30% of AD patients
mechanical trauma, e.g. scratching, infection or the activity of SP serum concentration exceeded the maximum concentration
inflammatory cytokines and proteases, e.g. papain and trypsin. The measured in healthy controls.
role of TLSP in direct stimulation of itch-sensory neurons in vivo Furthermore, chemokine C-X-C motif ligand 1 (CXCL1) has
was previously documented (26). The involvement of TLSP in been associated with atopic dermatitis, a highly pruritic skin
pathogenesis of AD was supported by the results of clinical study disease via not fully recognized mechanism (38). Recent
with tezepelumab, a human monoclonal antibody against TSLP. In evidence indicates that CXCL1 can activate the itch-sensitive
that study tezepelumab markedly attenuated the severity AD (27). subset of TRPV1+/IB4+ dorsal root ganglion (DRG) neurons (38).
Previously published studies have demonstrated that the House dust mites, cosmopolitan pyroglyphids, have been
blood concentration of TLSP was significantly higher in adult identified as a major cause of allergic diseases worldwide. More
AD patients, compared to healthy controls (28, 29). Similar than 30 HDM allergens have been recognized, among them the
results were obtained in the present study, where serum most prominent are cysteine proteases (Der p1 i Der f1) and
concentration of TSLP in AD patients was more than five times NPC 2 proteins (Der p2 i Der f2) (11).
higher than in control subjects. However, no correlation between The correlation between the number of HDMs on the skin
TSLP concentration and HDM classes was observed. and in patients' homes and AD severity has been known for years
Interleukin 25 is a newly discovered cytokine with structure (39, 40). The results of atopy patch tests with mite allergens
similar to cytokines from interleukin 17 family, therefore it is show it is possible to induce typical AD skin lesions in vivo,
sometimes referred to as IL-17E. IL-25 stimulates lymphocyte especially in areas exposed to these aeroallergens (air-exposed
Th2 to secrete IL-4, IL-5 and IL-13 in paracrine and autocrine distribution), as confirmed by the work of many researchers (41,
manner. IL-25 binds to the heterodimeric receptor composed of 42). Positive patch tests are associated with the presence of IgE
the IL 17 receptor B (IL-17RB), also known as IL 25R and IL- bearing Langerhans cells in the epidermis of atopic dermatitis
17RA, two members of the IL-17 family, expressed in a variety patients (43). AD patients that experienced delayed-type
of cells, including T cells, dendritic cells, macrophages, type-2 hypersensitivity reactions tended to demonstrate severe skin
myeloid cells, epithelial cells and eosinophils (11, 30). IL-25 symptoms and exhibit high total IgE levels as well as HDM-
targets group 2 ILCs, inducing secretion of IL-5 and IL 13 from specific IgE levels (41, 44). The impaired skin barrier in AD
these cells (31). An increased serum level of IgE was observed in leads to an increased epidermal permeability and penetration of
transgenic mice overexpressing IL-25 and this observation allergens and irritants through the skin (7). The key role of HDM
indicated that the said interleukin plays an important role in in AD development and exacerbation is related to the activity of
pathogenesis of autoimmune diseases like AD (10). It has been proteolytic enzymes, activation of proteinase-activated296
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