International Journal of

Molecular Sciences

Review
Advances in Understanding the Immunological
Pathways in Psoriasis
Simona-Roxana Georgescu 1,2 , Mircea Tampa 1,2, *, Constantin Caruntu 3,4, *,
Maria-Isabela Sarbu 1 , Cristina-Iulia Mitran 5 , Madalina-Irina Mitran 5 , Clara Matei 1 ,
Carolina Constantin 6,7 and Monica Neagu 6,7,8
1 Department of Dermatology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest,
Romania; [email protected] (S.-R.G.); [email protected] (M.-I.S.);
[email protected] (C.M.)
2 Department of Dermatology, Victor Babes Hospital of Infectious Diseases, 030303 Bucharest, Romania
3 Department of Physiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
4 Department of Dermatology, Prof. N.C. Paulescu National Institute of Diabetes,
Nutrition and Metabolic Diseases, 030167 Bucharest, Romania
5 Department of Microbiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest,
Romania; [email protected] (C.-I.M.); [email protected] (M.-I.M.)
6 Department of Immunology, Victor Babes National Institute of Pathology, 050096 Bucharest, Romania;
[email protected] (C.C.); [email protected] (M.N.)
7 Department of Pathology, Colentina University Hospital, 020125 Bucharest, Romania
8 Faculty of Biology, University of Bucharest, 030018 Bucharest, Romania
* Correspondence: [email protected] (M.T.); [email protected] (C.C.)




Received: 12 January 2019; Accepted: 8 February 2019; Published: 10 February 2019


Abstract: Psoriasis vulgaris is a chronic, immune-mediated, inflammatory, polygenic skin disorder

affecting approximately 2% of the population. It has a great impact on quality of life; patients often
experience depression, anxiety, stigma as well as suicidal behavior. Even though psoriasis is one of
the most studied dermatological conditions, the pathogenesis of the disease is still not completely
elucidated. The complex interactions between keratinocytes, dendritic cells, T-lymphocytes,
neutrophils and mast cells are responsible for the histopathological changes seen in psoriasis.
The pathogenic model leading to the formation of psoriatic plaques has however evolved a lot
over the years. There is now enough evidence to support the role of interleukin (IL) -23, IL-17, IL-22,
T helper (Th) -17 cells, Th-22 cells, T regulatory cells, transforming growth factor (TGF)-β1 and IL-10
in the pathogenesis of the disease. Moreover, several inflammatory and anti-inflammatory molecules
are currently being investigated, some of them showing promising results. The aim of this paper is to
look over the most recent advances in the immunological pathways involved in the pathogenesis of
psoriasis vulgaris.

Keywords: psoriasis; inflammation; immunology; Th-17; IL-17; T regulatory cells

1. Introduction
Psoriasis vulgaris is a chronic, immune-mediated, inflammatory, polygenic skin disorder affecting
approximately 2% of the population. It has a universal occurrence; males and females being equally
affected [1–4]. It can appear at any age, but two peaks in age of onset have been described: the first
between 20 and 30 years and the second between 50 and 60 years [4,5]. Plaque-type psoriasis accounts
for approximately 90% of cases and clinically manifests as well-demarcated erythematous plaques
covered by silvery-white scales with a predilection for the extensor surfaces of the extremities, scalp,

Int. J. Mol. Sci. 2019, 20, 739; doi:10.3390/ijms20030739 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2019, 20, 739 2 of 17

sacral area and umbilicus [3,6]. Psoriasis has a great impact on quality of life; patients often experience
depression, anxiety, stigma as well as suicidal behavior [7,8].
Even though psoriasis is one of the most studied dermatological conditions, the pathogenesis
of the disease is still not completely elucidated [9]. The complex interactions between
keratinocytes, dendritic cells (DCs), T-lymphocytes, neutrophils and mast cells are responsible for
the histopathological changes seen in psoriasis, namely elongated rete ridges, hyperkeratosis with
parakeratosis, Munros’ microabscesses and dilated vessels in the dermal papilla [10,11]. The pathogenic
model leading to the formation of the psoriatic plaque has however evolved a lot over the years. While
the disease was initially considered an epidermal disorder in which various mediators like cyclic
adenosine monophosphate, protein kinase C, phospholipase C, eicosanoids, transforming growth
factor (TGF)-α had a central role [6,7], in later years the role of T-cells was recognized and interferon
(IFN)-γ and interleukin (IL)-12 were considered key players in the pathogenesis of psoriasis [12].
Tumor necrosis factor (TNF)-α was also intensely studied and the biological therapies targeting this
cytokine revolutionized the treatment of psoriasis vulgaris [11,13]. More recently, studies point at the
cytokines of the IL-23/IL-17 axis as the important players in the pathogenesis of psoriasis [12]. The aim
of this paper is to look over the most recent advances in the immunological pathways involved in the
pathogenesis of psoriasis vulgaris.

2. Psoriasis Pathogenesis in Brief

Clinical and experimental data sustain the seminal role of the immune system in the pathogenesis
of this disease. Even though it is considered a T cell mediated inflammatory pathology, cells that
belong to both adaptive and innate immunity as well as non-immune cells are highly involved. Thus,
from the first category, dendritic cells, NK cells and macrophages were found as being involved
in the pathogenesis of psoriasis, along with cells from the second category; namely keratinocytes
and endothelial cells [14]. The autoantigens that activate autoimmune reactions in this disease are
still a matter of research. For example, LL-37, an antimicrobial peptide (AMP) that is produced
by keratinocytes upon injury, was found overexpressed in moderate to severe psoriatic forms [15].
Another possible auto-antigen could be ADAMTS-like protein 5, produced by injured melanocytes.
This auto-antigen can activate the Th17 response, maintaining the psoriatic condition [16].
There are two commonly acknowledged phases for the pathogenesis of psoriasis: the
initiation/triggering of the disease, and the maintenance of the pathological status [12]. In the
early phase, DCs are activated and start producing inflammatory mediators. Plasmacytoid DC
(pDCs) express Toll-like receptors (TLR)7 and TLR9 which normally recognize viral and microbial
acids and do not respond to self-DNA [17]. Under certain conditions, which include triggering
factors such as physical injury, keratinocytes produce excessive AMPs, such as β-defensins and
LL-37. Damaged cells also produce self-nucleic acids, self-DNA and self-RNA. LL-37 binds self-DNA
and forms complexes which are delivered in the early endocytic departments and which cannot be
degraded and are able to activate TLR9 and TLR7, inducing IFN-α production and triggering pDC
activation. On the other hand, self-RNA and LL-37 complexes stimulate myeloid DCs to mature
after the production of TNF-α and IL-6 [12,18]. Once activated, DCs are transformed into mature
antigen presenting cells and start producing cytokines like TNF-α, IL-23 and IL-12 and are therefore
able to interact with T naive cells. IL-23, in association with IL-6 and TGF-β1, will determine the
transformation of CD4+ naive cells to Th-17 which will produce IL-17, IL-22 and TNF-α. IL-23,
in association with IL-6 and TNF-α, also promotes the production of Th-22 cells which secrete IL-22
and TNF-α [19]. All these mediators further maintain keratinocytes activation producing the now
so-called auto-antigen, LL-37, proinflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines and
S100 proteins, propagating the chronic inflammation [20]. Altogether, these promote keratinocyte
proliferation, production of AMPs and chemokines which promote neutrophil recruitment and sustain
skin inflammation (Figure 1) [12,21–24].
Int. J. Mol. Sci. 2019, 20, 739 3 of 17
Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 17

Figure 1. Cytokine network in psoriasis. IFNα = interferon-α, IFNγ = interferon-γ, IL-6

Figure 1. Cytokine network in psoriasis. IFNα = interferon‐α, IFNγ = interferon‐γ, IL‐6 =
= interleukin-6, IL-8 = interleukin-8, IL-12 = interleukin-12, IL-17 = interleukin-17, IL-22 =
interleukin‐6, IL‐8 = interleukin‐8, IL‐12 = interleukin‐12, IL‐17 = interleukin‐17, IL‐22 =
interleukin-22, IL-23 = interleukin 23, LL37 = cathelicidin, PMN = polymorphonuclears, S 100 =
interleukin‐22, IL‐23 = interleukin 23, LL37 = cathelicidin, PMN = polymorphonuclears, S 100 = S
S 100 proteins, Th1 = T helper 1, Th17 = T helper 17, Th22 = T helper 22, TGFβ = transforming
100 proteins, Th1 = T helper 1, Th17 = T helper 17, Th22 = T helper 22, TGFβ = transforming growth
growth factor-beta, Tn = naïve T lymphocyte, TNFα = tumor necrosis factor-α, and TNFβ = tumor
factor‐beta, Tn = naïve T lymphocyte, TNFα = tumor necrosis factor‐α, and TNFβ = tumor necrosis
necrosis factor-β.
factor‐β.
3. Activators of Inflammation in Psoriasis
3. Activators of Inflammation in Psoriasis
3.1. Cytokines
3.1. Cytokines
3.1.1. IL-23
3.1.1.IL-23
IL‐23is part of the IL-6/IL-12 family of heterodimeric cytokines and is composed of a p40 subunit,
which is shared
IL‐23 is partwith
of theIL-12, and a unique
IL‐6/IL‐12 familyp19 subunit [12,25,26].
of heterodimeric IL-23 and
cytokines is involved in the of
is composed immune
a p40
response againstisbacteria
subunit, which shared and withfungi
IL‐12,andandis produced
a unique byp19several
subunit cells, including
[12,25,26]. keratinocytes,
IL‐23 is involveddermal
in the
myeloid
immune cells and macrophages
response against bacteria[12,26].and Thefungi
cytokine
andexerts its action by
is produced through a receptor
several complex
cells, including
which is composed
keratinocytes, dermal ofmyeloid
the IL-23R subunit
cells and the IL-12Rβ1
and macrophages [12,26].subunit,
The cytokinecommon with
exerts IL-12. IL-23
its action throughactsa
on cells expressing
receptor complex which IL-23R, namely memory
is composed T cells,
of the IL‐23R mast cells,
subunit and the macrophages, neutrophils,
IL‐12Rβ1 subunit, common natural
with
killer
IL‐12. (NK)
IL‐23cells
actsand
on keratinocytes
cells expressing [12,25]. The phosphorylation
IL‐23R, namely memory ofT Signal cells, Transducer
mast cells, and Activator
macrophages,
of Transcription
neutrophils, (STAT)
natural is required
killer (NK) cellsfor signal transmission,[12,25].
and keratinocytes STAT-3 The beingphosphorylation
particularly important
of Signalin
psoriasis [25]. IL-23 has a paramount importance in maintaining the cytokine
Transducer and Activator of Transcription (STAT) is required for signal transmission, STAT‐3 being milieu required for
the survivalimportant
particularly of Th-17 cells [27]. Naive
in psoriasis [25].T-cells
IL‐23 hasdo anot express IL-23R
paramount importanceand therefore cannotthe
in maintaining becytokine
directly
activated by IL-23.
milieu required for In
thethe presence
survival of of a combination
Th‐17 of cytokines
cells [27]. Naive T‐cells naive
do notT-cells
expressdifferentiate
IL‐23R andinto Th-17
therefore
cells [27,28]. The model behind Th-17 differentiation is different in mice
cannot be directly activated by IL‐23. In the presence of a combination of cytokines naive T‐cells versus humans. In the
murine model,
differentiate IL-6
into andcells
Th‐17 TGF-β induce
[27,28]. Thenaive
model murine
behindT-cells
Th‐17to differentiate into
differentiation Th-17 cells
is different andversus
in mice IL-21,
IL-23,
humans. TNF-α
In theand IL-1βmodel,
murine amplifyIL‐6the
anddevelopment
TGF‐β induce of those cells. InT‐cells
naive murine the human model, the
to differentiate optimal
into Th‐17
cells and IL‐21, IL‐23, TNF‐α and IL‐1β amplify the development of those cells. In the human model,
the optimal conditions for Th‐17 differentiation are less clear and multiple combinations of cytokines
Int. J. Mol. Sci. 2019, 20, 739 4 of 17

conditions for Th-17 differentiation are less clear and multiple combinations of cytokines have been
described, including IL-1β and IL-6 or IL-23 and IL-1β. Moreover, in humans, the role of TGF-β in the
differentiation of Th-17 cells is controversial [29].
Studies showed increased levels of IL-23, subunits p19 and p40 in psoriatic skin compared to
non-lesioned skin [28]. Biological treatments targeting IL-23 are now intensely studied for the treatment
of psoriasis and the preliminary results are promising [30].

3.1.2. IL-1β
IL-1β is mainly produced by monocytes, macrophages, Langerhans cells and dendritic cells.
It exerts its activity by binding to its receptor which is composed of the IL-1 receptor type 1 (IL-1R1)
and IL-1 receptor accessory protein (IL-1RAcP). Activated IL-1R1 binds to the adaptor protein Myeloid
differentiation primary response gene 88 and activates one or more Interleukin-1 receptor-associated
kinases (IRAKs) [1]. Since IL-1β is a well-known initiator and effector for inflammation, several proteins
involved in the production of this interleukin in psoriasis were investigated. CCN1 (cysteine-rich
protein 61), a protein involved in inflammation, cell proliferation and angiogenesis, among others,
was shown to be upregulated in psoriasis skin lesions and to promote keratinocyte proliferation via
the α6β1/PI3K/Akt/NF-κB pathway, but was also shown to increase the production of IL-1β via the
p38 MAPK signaling pathway. This suggests that CCN1 plays a role in the pathogenesis of psoriasis
and in modulating inflammation in the disease [31]. In psoriasis, IL-1β maturation is mediated by
ASC (Apoptosis-associated speck-like protein containing a caspase recruitment domain) -dependent
inflammasome complexes, such as NLRP3 and AIM2, which activate caspase-1. However, NLRP-1,
a subset of the NLR family inflammasomes, can further activate IL-1β by utilizing IL-17A promoted
caspase-5, independently from ASC-dependent inflammasome. Therefore, caspsase-5 and NLRP-1 are
potential targets for new psoriasis therapies [32].

3.1.3. IL-17
IL-17A plays a leading role in the pathogenesis of psoriasis. It is a member of the IL-17
family which comprises six members, namely IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F.
IL-17A and IL-17F are the most closely related and have overlapping biological functions. IL-17A is
produced by Th17 cells, NK cells, γδT cells and innate lymphoid cells (ILCs), but also myeloid
cells, B-cells, mast cells, neutrophils and macrophages. IL-17A and IL-17F signal through the
heterodimeric receptor IL-17RA/IL-17RC which is located on keratinocytes, endothelial cells and
fibroblasts [12,33–36]. IL-17A and IL-17F are involved in the protection against infections on epithelial
and mucosal surfaces, especially staphylococcus and candida infections, and are key drivers in skin
inflammation [33]. After binding to IL-17RA/IL-17RC, IL-17A determines the expression of AMPs
like β-defensins, S100 proteins, LL37 and Lipocalin-2 (Lcn2), GM-CSF (Granulocyte-macrophage
colony-stimulating factor), chemokines like CCL20, CXCL-1, CXCL-3, CXCL-5, CXCL-8, CCL-20,
matrix metalloproteinases (MMP) and proinflammatory cytokines like IL-6, TNF-α and IL-1F9. CXCL-1,
CXCL-3, CXCL-8 and AMP are involved in the recruitment of neutrophils at the infection site while
CCL20 recruits Th-17 cells and ILC3 [12,33]. An aberrant production of IL-17A disrupts the appropriate
immune responses and promotes the development of various inflammatory diseases, including
psoriasis, rheumatoid arthritis, Crohn’s disease, etc. [35]. AMPs, cytokines and chemokines produced
due to IL-17A have an important role in the formation of the psoriatic plaque [37].
Previous studies showed that IL-17 levels are increased in psoriatic patients [38,39] and the role
of the interleukin in psoriasis is further supported by the favorable results obtained with biological
agents targeting IL-17 [35,40,41].
Even though IL-17A and IL-17F are the most important of the IL-17 family members involved in
the pathogenesis of psoriasis, IL-17E is also increased in keratinocytes from the psoriasis plaque and
seems to play a proinflammatory role, as it is implicated in macrophage activation [42].
Int. J. Mol. Sci. 2019, 20, 739 5 of 17

IL-17 has also been linked to cardiovascular disease and other inflammatory comorbidities.
Therefore, targeting this interleukin might be associated with supplementary benefits for the psoriatic
patient [23].

3.1.4. IL-22
IL-22 is a member of the IL-10 family and plays an important role in the homeostasis of
mucosa and barrier organs, as it has anti-bacterial, anti-fungal, anti-viral and anti-inflammatory
activities. It is produced by Th-17, ILC3, mast cells, dermal γδ T cells, but also Tc-17 and Th-17
cells [43,44]. IL-22 receptors are made up of IL-22R1 and IL-10R2 subunits. IL-22R1 are restricted to
non-hematopoietic cells. After IL-22 binds to the IL-22R complex, signal transmission is performed
through the phosphorylation of STAT3 and the activation of the ERK1/2 pathway [45]. IL-22 production
depends on IL-23 and transcription factors RORγt, but most importantly, AhR (aryl hydrocarbon
receptor). AhR is a ligand transcription factor in Th-17 cells which is mandatory for the production of
IL-22 by those cells. In psoriasis, the expression of IL-22 is increased and its effects are mostly directed
towards regulating keratinocyte functions [12]. Therefore, IL-22 is involved in enhancing keratinocyte
migration, increasing epidermal thickness by interfering with physiological desquamation, producing
chemokines, AMPs, neutrophil chemoattractants and inducing production of MMPs [12,45]. Since
IL-22 has a well-established role in the pathogenesis of psoriasis, this interleukin is a potential target
for psoriasis treatments [45–47].

3.1.5. IFN-γ
INF-γ is a type II interferon involved in innate and adaptive immunity against viral and
intracellular bacterial infections [48]. Major sources of IFN-γ are activated Th-1 cells, CD8 T cells,
NK cells and dendritic cells. The production of this cytokine is mostly controlled by IL-12 and IL-18
and macrophages, dendritic cells and naive T cells are the main responsive cells [1,49]. IFN-γ exerts
its action through the IFN-γ receptor (IFNGR) which consists of two transmembrane chains: IFN-γ
R1 and IFN-γ R2 [50] and primarily signals through the JAK-STAT pathway [49]. High levels of
IFN-γ mRNA were identified in psoriasis lesions and psoriatic blood [51,52]. Kryczek et al. found
that in humans, IFN-γ programs myeloid antigen presenting cells to produce IL-1 and IL-23 and to
induce human IL-17+T cells [53]. In a study performed on 21 participants with psoriasis, the authors
found a correlation between IFN-γ levels and disease severity measured by psoriasis area and severity
index (PASI). Furthermore, IFN-γ was shown to be a prognostic factor for psoriasis [54]. However, in a
study performed on 20 patients with psoriasis the authors found that treatment with a neutralizing
anti-IFN-γ antibody had minimal efficacy and concluded that IFN-γ is not a major pathogenic cytokine
in psoriasis lesions [55].

3.2. T-Cells

3.2.1. Th-17 Cells

Th-17 cells are special populations of CD4+ T cells that produce IL-17, IL-22, IL-21, TNF-α
and other cytokines, and express lineage specific transcription factor Retinoic acid receptor-Related
Orphan receptor (RORC) [25,26,56,57]. The family of Th-17 cells includes several cell types, all of
them expressing ROR-γt and IL-23R. Th-17 cells activated by IL-6, IL-1β and IL-23 trigger chronic
inflammation and autoimmunity while TGF-β and IL-6 activated Th-17 cells are weakly pathogenic
and are mostly involved in tissue integrity and defense [57–59].

3.2.2. Th-22 Cells

Th-22 cells are a distinct subset of inflammatory CD4+ T cells with a unique expression profile
and a novel functional spectrum. They produce IL-22, TNF-α, IL-13 and IL-26, but not IFN-γ or
IL-17. The Th-22 phenotype can be promoted by TNF-α and IL-6 [60,61]. Additionally, they express
Int. J. Mol. Sci. 2019, 20, 739 6 of 17

chemokine receptors like CCR4 and CCR6 and are influenced by IL-23. Since the expression of IL-22
is the main feature of these cells, they were attributed the name Th-22 cells [45]. Increased levels
of Th-22 [62], as well as Th-17, were identified in psoriasis vulgaris and psoriatic arthritis [63]. In a
study performed on 60 patients with psoriasis and 30 healthy controls, the authors found significantly
higher levels of IL-6, IL-20 and IL-22 in psoriatic patients than in the control group, the concentrations
of IL-20 and IL-22 being positively correlated with disease severity measured with PASI and body
surface area (BSA). The authors therefore concluded that the Th-22 response might contribute to the
inflammatory disease in psoriasis [61]. Moreover, Cheuk et al. showed in a study published in 2014
that epidermal Th-22 and Tc-17 are retained in healed psoriasis and can produce cytokines involved in
psoriasis pathogenesis, thus promoting disease recurrence in previously affected areas [64].

3.2.3. Th-1 Cells

Th-1 cells are CD4+ T cells which produce IFN-γ, IL-2 and TNF and are the main carriers
of cell-mediated immunity. Infections by intracellular bacteria and viruses are responsible for the
production of Th-1 cells. IL-12 determines the differentiation of naive Th cells into Th-1 cells and
enhances the production of IFN-γ [1,65]. While Th-17 cells play an important role in the initiation
phase of the disease, Th-1 cells/IFN-γ-associated inflammation predominate in chronic plaques [66].

3.3. Other Molecules

RORC/RORγt
RORC is expressed on various immune cells and is a key factor in the differentiation of Th-17
cells. Animal studies have shown that RORγt (Retinoid-related orphan nuclear receptor gamma t,
a ROR found in mice) deficient mice have decreased Th-17 cell differentiation associated with reduced
inflammation [67]. In a study published in 2018, the authors determined the mRNA expression
level of RORC in patients with psoriasis and found significantly higher gene expression of RORC in
patients with psoriasis than in controls, thus concluding that Th-17 plays a role in the pathogenesis of
the disease [56]. RORγt antagonists and inverse agonists are now being tested for the treatment of
psoriasis [68].

4. Regulatory Axis in Psoriasis

4.1. Treg Cells

T regulatory (Treg) cells, more specifically the abnormalities in the Th17/Treg balance, were also
shown to be key players in the pathogenesis of psoriasis [69]. Treg cells are a heterogenous group of T
lymphocytes responsible for suppressing an excessive or autoreactive immune response, thus playing
an important role in immunological tolerance [69,70]. Several regulatory cells populations have been
described in humans, including regulatory B cells, NK-T cells, myeloid derived suppressor cells and
CD8+ regulatory T cells, the most important however being a subset of T helper (CD4+) regulatory
cells. The main phenotypic characteristics of Treg cells are the high expression of the CD25 receptor,
the expression of the transcription factor forkhead box P3 (FOXP3) and the production of IL-10 and
TGF-β [12,70]. Treg cells interact with other cells by producing suppressing cytokines like IL-10, IL-35
or TGF-β, by releasing granzyme B or perforin which have a direct cytotoxic action or through cell
receptors [69]. Naive Treg cells can differentiate into Th1-Treg, Th2-Treg, Th17-Treg, Fat-Treg and
Tfr-Treg which suppress Th-1, Th-2, Th-17, adipocytes and T-cells in the germinal centers of lymphoid
tissue [70]. When the promoters of IL-10, IL-35, TGF-β1, CTLA4 (T-lymphocyte–associated antigen 4)
and CD25 genes are activated and the promoters of IL-2, IL-4 and INF-γ are blocked, the produced
Treg cells are suppressive [71]. FOXP3 mutations, which result in the absence or an inadequate number
of Treg cells, manifests as IPEX syndrome: immune dysregulation, polyendocrinopathy, enteropathy
and X-linked syndrome [70,71].
Int. J. Mol. Sci. 2019, 20, 739 7 of 17

Abnormalities in Treg cells have been associated with inflammation in psoriasis. Therefore, by
producing IL-10, Treg cells downregulate the expression of proinflammatory cytokines, chemokines
and adhesion molecules and decrease inflammation [12]. A study performed on patients with plaque
and guttate psoriasis found higher levels of FOXP3 positive Treg cells in skin lesions and peripheral
blood of patients with plaque type psoriasis, the levels being positively correlated with disease
severity [72]. Other authors also identified higher levels of FOXP3 positive Treg cells and Th-17 in
the psoriatic lesions and the peripheral blood, thus indicating a possible role in the pathogenesis of
psoriasis [73,74]. However, some authors found lower levels of Treg cells not only in the peripheral
blood of psoriatic patients [75], but also in skin samples [70]. Since the presence of Treg cells in the
psoriatic plaque was not associated with a decrease in inflammation, several authors investigated
those cells. Soler et al. showed in a study published in 2013 that psoriatic Treg cells are numerically,
functionally and chemotactically deficient and are therefore unable to restrain inflammation [76].
Moreover, it has been shown that under proinflammatory conditions, Treg cells can differentiate into
Th-17 cells. In the presence of IL-6 and TGF-β, naive T cells upregulate both FOXP3 and RORγt. Thus,
Treg and Th-17 subtypes compete for the same T cell precursor which upregulates FOXP3 and RORγt
depending on the cytokine repertoire from the psoriatic milieu. Considerably increased in psoriasis,
IL-23 is a pro-inflammatory cytokine attributed to regulate Treg cells via STAT3 pathway activation,
thus disturbing Treg cell function, recognized as a hallmark of psoriasis [69]. Bovenshen et al.
therefore showed that FOXP3 positive Treg cells from psoriasis lesions can differentiate into a strong
proinflammatory triple positive IL-17A+/Foxp3+/CD4+ Th-17 which perpetuates the inflammatory
process [77].
Micro-RNAs (miRs) are a group of small, endogenous, non-coding RNAs, composed of
approximately 21–23 nucleotides, which negatively regulate gene expression at the posttranscriptional
level. More than 2500 miRs have been identified in humans. Of those, miR-210 is significantly increased
in the peripheral blood mononuclear cells and skin lesions of patients with psoriasis [78,79]. In a study
published in 2014, the authors reported that microRNA-210 is overexpressed in CD4+ T cells from
psoriatic patients and that it inhibits expression of FOXP3, thus impairing the immunosuppressive
function of Treg cells. Moreover, miR-210 inhibition reverses the immune dysfunction [80]. Regulation
of miR-210 expression in psoriasis has direct consequences on immune dysfunction exerted by Tregs.
Thus, in a recent study performed on mice, Wu et al. showed that miR-210 ablation and its inhibition
by antagomir-210 blocks the immune imbalance and the development of the psoriatic plaque [79].
A specific role in miR-210 effect is attributed to hypoxia-inducible factor-1α (HIF-1α) a transcription
factor known to modulate genes associated to hypoxic milieus [81]. In addition, in psoriasis HIF1α
is known to induce miR-210 overexpression at CD4+ T cells level mediated by TGF-β and IL-23.
HIF1α act in an epigenetic manner by causing hyperacetylation of histone H3 in the miR-210 gene
promoter revealing a potentially upstream regulatory mechanism of miR-210 overexpression. These
data endorse miR-210 for a proinflammatory role in inducing immune imbalance and skin lesion
presence in psoriasis [79].

4.2. TGFβ
TGFβ is a multipotent growth factor involved in maintaining immune homeostasis. It inhibits the
activity of macrophages and neutrophils, promotes angiogenesis and the proliferation of fibroblasts and
regulates T cells subpopulations [69]. Three isoforms are currently recognized, respectively TGFβ-1,
TGFβ-2 and TGFβ-3, which bind to their receptors, TGFβRI, TGFβRII and TGFβRIII. Of those, TGFβ1
is predominantly found in the skin [82]. Studies showed that elevated serum levels of TGF-β1 are found
in psoriatic patients and that those levels are correlated with disease severity [83,84]. TGFβ-1 was
considered an anti-inflammatory cytokine. However, its overexpression in keratinocytes was shown
to induce skin inflammation and the development of psoriasis-like lesions via a Smad-dependent
mechanism [82,85]. In patients with psoriasis, TGFβ-1 induces the generation of FOXP3 positive Treg
cells in the absence of IL-6 and the production of Th-17 cells in the presence of IL-6 [86]. While the
Int. J. Mol. Sci. 2019, 20, 739 8 of 17

exact role of TGF-β in the pathogenesis of psoriasis is not completely understood, data available so
far suggests that it might be a good biomarker for the severity of psoriasis and treatments targeting
Smad3 might be associated with favorable results [7].

4.3. IL-10
IL-10 is probably one of the most potent anti-inflammatory cytokines and has an important
role in immune mediation. Its part in modulating the immune response to microbial flora raised
the suspicion that it is involved in the pathogenesis of various inflammatory diseases, including
psoriasis [87]. Macrophages are the most important source of IL-10, but it is also secreted by B cells,
T cells, mast cells, dendritic cells, keratinocytes, eosinophils and NK cells, among others [87,88].
Moreover, there are recent studies that link psoriasis onset with mutations in the promoter region of the
IL-10 gene [89]. IL-10 performs its regulatory actions through the modulation of antigen presentation
in dendritic cells, suppression of T cell activity and stimulation of B cell differentiation [87,88]. Studies
performed in patients with psoriasis showed that the levels of IL-10 are decreased in the patients’
serum [90,91]. In a study performed on peripheral blood B regulatory cells (Bregs) from 60 patients
with psoriatic arthritis, 50 patients with psoriasis and 23 healthy controls, the authors found that IL-10
producing Bregs were decreased in patients with psoriasis and psoriatic arthritis and that they were
inversely correlated with disease severity [92]. Various psoriasis treatments have been associated
with an increase in the levels of IL-10. Zanin-Zhorov et al. showed that the oral administration of
KD025, a selective inhibitor of Rho-associated kinase (ROCK)2—a serine/threonine kinase protein
involved in regulation of autoimmunity—leads to a decrease in disease severity measured by PASI,
a decrease in pro-inflammatory cytokines IL-17 and IL-23 and an increase in IL-10 levels after 10 weeks
of treatment [93]. Cyanobacterium aponinum, a member of the microbial ecosystem of the Blue Lagoon in
Iceland, was also shown to have beneficial effects in psoriasis. In a study published in 2015, the authors
found that exopolysaccharides (EPSs) secreted by C. aponinum determines the maturation of dendritic
cells, increased the levels of IL-10 and the frequency of FoxP3(+)IL-10(+) T cells and decreased the
IL-17(+)RORγt(+)/FoxP3(+)IL-10(+) ratio. The authors therefore concluded that bathing in the Blue
Lagoon could be advantageous for psoriatic patients [94]. All this data supports the role of IL-10 in
the pathogenesis of psoriasis and supports the idea that targeting IL-10 might be useful in psoriasis.
Further data is however required.

5. Additional Inflammatory Pathways in Psoriasis

There are several recent pro-inflammatory pathways that were linked to psoriasis pathogenesis.
ACKR2 (Atypical chemokine receptor 2), previously known as the chemokine-scavenging receptor D6,
is a scavenger receptor for CC chemokines that has been associated with various inflammatory diseases,
including psoriasis. In the skin, ACKR2 is expressed by keratinocytes and dermal lymphatic endothelial
cells. Unlike other chemokine receptors, ACKR2 are unable to mount typical signaling responses
to chemokines, but instead internalize and degrade inflammatory chemokines [95]. Singh et al.
observed that this receptor is markedly expressed in uninvolved psoriatic skin and that inflammatory,
but non-functional, CC chemokines are also increased in uninvolved skin. The authors therefore
concluded that ACKR2 plays a part in suppressing chemokine-driven inflammatory responses [96].
Shams et al. managed to link altered ACKR2 expression in psoriasis to miR-146 and miR-10b,
two microRNAs that directly bind ACKR2 30 -untranslated region and decrease the expression of
ACKR2 transcripts in keratinocytes and lymphatic endothelial cells. Furthermore, the authors showed
that cell trauma, a well-known trigger for psoriasis, also leads to decreased expression of ACKR2 [97].
Animal studies found that mild inflammation and IFN-γ administration are able to increase ACKR2
expression and restrict inflammation. ACKR2 induction might therefore be a promising therapeutic
strategy in psoriasis [98].
Even though psoriasis is considered a T cell mediated disease, some authors investigated the
potential role of B cells in the pathogenesis of psoriasis. In a study published in 2016, the authors
Int. J. Mol. Sci. 2019, 20, 739 9 of 17

reported higher levels of CD19+ B cells in the peripheral blood of psoriatic patients than in healthy
controls. Moreover, CD19+ B cells ratios were positively correlated with disease severity and
the authors therefore concluded that B cells might play a role in different pathological stages of
psoriasis [99]. B regulatory cells are a subset of B cells that can negatively regulate immune responses.
In a study performed on mice, the authors showed that the skin inflammation induced by imiquimod
was more severe in CD19−/− mice than in wildtype mice and that regulatory B cells can suppress
the psoriasis-like inflammation [100]. Depletion of B cells with rituximab was associated with the
development of a psoriasis-like eruption in a patient treated for autoimmune lymphoproliferative
syndrome type III [101]. On the other hand, in a study published in 2018 by Thomas et al., the authors
concluded that B cells alterations are only an epiphenomenal finding in psoriasis [102]. Further studies
are therefore needed to support the role of B cells in psoriasis disease specific inflammation.
Beside those, panoply of molecules and cells with a potential role in the pathogenesis of psoriasis
has recently been investigated. We will further discuss some of the most recent findings in both
humans and animal models (Table 1).
Harden et al. explored the expression of the tryptophan metabolism enzyme L-kynureninase
(KYNU) in psoriatic human skin, normal human skin, blood cells and primary cells and found KYNU+
cells in psoriatic lesional cells, their expression being positively correlated with disease activity [103].
CD5+ dendritic cells, which can activate cytotoxic T cells and Th22 cells, were also found in higher
levels in skin biopsies from patients with psoriasis than in biopsies from adjacent uninvolved skin,
thus suggesting their role in the disease [104]. Buerger et al. showed in a study published in 2017
that mTOR signaling, which is normally deactivated when keratinocytes switch from proliferation to
terminal differentiation, under inflammatory conditions have an aberrant activity leading to enhanced
proliferation [105]. Nuclear receptor interacting protein 1 (NRIP1), a co-regulator for numerous nuclear
receptors, was found to be overexpressed in psoriatic lesions and in peripheral blood mononuclear cells
of patients with psoriasis. Moreover, animal studies showed that imiquimod-induced inflammation
was delayed in knockout NRIP1 mice. The authors suggested that NRIP1 could induce abnormal
proliferation and apoptosis of keratinocytes through direct interaction with Re1A/p65 [106].
In a mouse preclinical model, Andrianne et al. studied the expression of tristetraprolin (TTP),
an RNA-binding protein encoded by Zfp36 gene which regulates the mRNA stability of some cytokines,
in keratinocytes and explored its role in the imiquimod-induced psoriasis model. The authors
found that TTP deficiency is associated with systemic inflammation, skin lesions and psoriasis
related arthritis [107]. Deficiency of VISTA (V-domain Immunoglobulin Suppressor of T cell
Activation), an inhibitory immune checkpoint protein which suppresses CD4+ and CD8+ T cell
activation, was also associated with exacerbated psoriasiform inflammation due to hyperactivation
of Erk1/2 and Jnk1/2 and increased production of IL-23 [108]. In an imiquimod-induced psoriatic
mouse model, Surcel et al. have shown that in both peripheral blood and secondary lymphoid
organs disease development is associated with a significantly increased T-CD8a+ and NK1.1+
cell percentages while decreased T-CD4+ and B lymphocyte percentages [109]. Furthermore,
the deficiency of TWEAK, a molecule of the TNF superfamily [110], the overexpression of
Glucocorticoid-induced Leucine Zipper (GILZ) [111], prokineticin 2 (PK2) [112], upregulation of
ANGPTL6 [113], Human β-Defensin 3 and Murine β-Defensin [114] were shown to have an
inflammatory effect while the natural plant antimicrobial solution (PAM) [115], the endoribonuclease
MCPIP1 [33], the flavone Luteolin-7-glucoside (LUT-7G) [46], Heme oxygenase-1 (HO-1) [116],
the flavonoid Astilbin [117], Paeoniflorin (PF) and Paeonol (PN)-ingredients from plants used in
Traditional Chinese Medicine [118,119], superoxide dismutase (SOD3)-transduced Mesenchymal Stem
Cells [120] have an anti-inflammatory effect.
Int. J. Mol. Sci. 2019, 20, 739 10 of 17

Table 1. Overview of the cell/molecule that induces a particular effect and the subsequent model used
to demonstrate the effect.

Biological Effect Cell/Molecule/Pathway Model Used to Demonstrate the Effect Reference

Cell-Type Involvement/Effects
CD5+ dendritic cell by inducing cytotoxic T cells and Skin samples from psoriatic patients and
Inflammation [104]
Th22 cells healthy controls
Significantly increased peripheral T-CD8a+
Samples from imiquimod experimental
Inflammation lymphocyte and NK1.1+ cell percentages, decreased [109]
psoriasis mouse model
peripheral T-CD4+ and B lymphocyte percentages.
Cytokines/Chemokines-Type Effects
TWEAK-deficient mice bred on the
Inflammation TWEAK (TNF superfamily molecule) C57BL/6 background; Fn14-deficient [110]
mice bred on BALB/c background
Skin biopsies from psoriatic patients;
MCPIP1/Regnase-1 via restriction of IL-17A and
Anti-inflammatory Zc3h12a−/− mice; Il17ra−/− mice; [33]
IL-17C signaling
Il17a−/− mice.
Bioactive Molecules-Type Effects
Skin and blood samples from psoriatic
Inflammation Upregulated L-kynureninase (KYNU) [103]
patients and healthy controls
Skin and blood samples from psoriatic
Nuclear receptor interacting protein 1 (NRIP1) via
Inflammation and healthy patients; HaCaT cells; [106]
the regulation of RelA/p65
C57BL/6J (B6) and Nrip1−/− mice
Spontaneously immortalized human
Inflammation aberrant mTORC1 signaling keratinocyte cell line (HaCaT); NHK [105]
(normal human keratinocytes).
Zfp36-deficient mice (Zfp36−/− );
LoxP-flanked Zfp36 mice (Zfp36fl/fl );
Inflammation Tristetraprolin (TTP) deficiency [107]
LysM-Cre mice; CD11c-Cre mice; K14-Cre
mice; Zfp36∆EP Tnf ∆EP mice
VISTA (V-domain Immunoglobulin Suppressor of T
Inflammation cell Activation) deficiency via hyperactivation of C57BL/6 mice; Vsir−/− mice [108]
Erk1/2 and Jnk1/2.
Overexpression of GILZ (Glucocorticoid-induced
Inflammation GILZ-Tg (transgenic)mice; GILZ-Wt [111]
Leucine Zipper) via activation of TGF-β1
High expression of PK2 (prokineticin 2) induces K14-VEGF transgenic mice; Kunming
Inflammation [112]
production of IL-1 in macrophages mice; C57BL/6 mice
Upregulation of epidermal ANGPTL6 promotes K14-Angptl6 Tg mice; skin biopsies from
Inflammation [113]
hyperproliferation of keratinocytes psoriasis patients.
Human β-Defensin 3 and Murine β-Defensin 14 via Skin biopsies from psoriatic patients;
Inflammation [114]
Langerhans cell activation C57BL/6 mice.
PAM (plant antimicrobial solution) via inhibition of
Anti-inflammatory HaCaT cells; Female BALB/c mice [115]
inflammatory NF-κB signaling pathway
Luteolin-7-glucoside via inhibition of IL-22/STAT3 HEKn cells (Human Epidermal
Anti-inflammatory [46]
pathway Keratinocytes, neonatal); C57BL/6 mice
Astilbin inhibits Th17 cell differentiation via
Anti-inflammatory BALB/c mice [117]
Jak3/Stat3 signaling pathway
Heme oxygenase-1 (HO-1) by negative regulation of HaCaT cells; biopsies from psoriatic
Anti-inflammatory [116]
STAT3 signaling patients; BALB/c mice
Paeoniflorin by regulating Th17 cell response via
Anti-inflammatory BALB/c mice; C57BL/6 mice [118]
phosphorylation of STAT3
Paeonol by inhibiting the maturation and activation
Anti-inflammatory BALB/c mice [119]
of DC via the TLR7/8 signaling pathway
Superoxide dismutase (SOD3)-transduced MSCs
(Mesenchymal Stem Cells) via inhibition of signaling
pathways toll-like receptor-7, nuclear factor-kappa B,
Anti-inflammatory C57BL/6 mice [120]
p38 mitogen-activated kinase, and Janus
kinase–signal transducer and activator of
transcription

6. Conclusions
Psoriasis is an immune-mediated, inflammatory, polygenic skin disorder with a great impact on
patients’ quality of life. Despite being one of the most studied dermatological afflictions, the exact
Int. J. Mol. Sci. 2019, 20, 739 11 of 17

pathogenic mechanism leading to disease associated inflammation is still not completely understood.
There is now enough evidence to support the role of IL-23, IL-17, IL-22, Th-17 cells, Th-22 cells,
and TGF-β1 in the pathogenesis of the disease. Moreover, several inflammatory and anti-inflammatory
molecules are currently being investigated, some of them showing promising results. One should,
however, keep in mind that many of those molecules are involved in normal physiological processes
and/or in fighting viral, bacterial or fungal infections, among others. Inhibiting some of those
molecules might therefore be associated with adverse events. The development of novel, efficient
topical treatments could potentially help reduce the frequency of unwanted reactions.
Identifying new pieces in the puzzle represented by the cells and cytokines involved in the
pathogenesis of psoriasis might help identify new biomarkers for disease diagnosis and assessment
and new, potentially better, treatments.

Author Contributions: All authors have equally contributed to the writing and editing of the manuscript.
Funding: This research and APC was funded by projects of the Ministry of Research and Innovation in Romania,
under Program 1—The Improvement of the National System of Research and Development, Subprogram
1.2—Institutional Excellence—Projects of Excellence Funding in RDI, Contract No. 7PFE/16.10.2018 and
PN.19.29.01.01/2019, and by UEFISCDI Project PN-III-P1-1.2-PCCDI-2017-0341.
Conflicts of Interest: The authors declare no conflict of interest.

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