The Inflammatory Response in Psoriasis: a ComprehensiveReview

Yaxiong Deng1 & Christopher Chang2 & Qianjin Lu1,3

Published online: 30 March 2016# Springer Science+Business Media New York 2016

Abstract Psoriasis is a chronic inflammatory autoimmune dis-ease characterized by an excessively aberrant hyperproliferationof keratinocytes. The pathogenesis of psoriasis is complex andthe exact mechanism remains elusive. However, psoriasis isthought to result from a combination of genetic, epigenetic,and environmental influences. Recent studies have identified thatepigenetic factors including dysregulated DNA methylationlevels, abnormal histone modification and microRNAs expres-sions are involved in the development of psoriasis. The interplayof immune cells and cytokines is another critical factor in thepathogenesis of psoriasis. These factors or pathways includeTh1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasisdue to its pro-inflammatory effects and its involvement in anintegrated inflammatory loop with dendritic cells andkeratinocytes, contributing to an overproduction of antimicrobialpeptides, inflammatory cytokines, and chemokines that leads toamplification of the immune response. In addition, other path-ways and signaling molecules have been found to be involved,including Th9, Th22, regulatory Tcells,γδTcells, CD8+ Tcells,and their related cytokines. Understanding the pathogenesis ofpsoriasis will allow us to develop increasingly efficient targeted

treatment by blocking relevant inflammatory signaling pathwaysand molecules. There is no cure for psoriasis at the present time,and much of the treatment involves managing the symptoms.The biologics, while lacking the adverse effects associated withsome of the traditional medications such as corticosteroids andmethotrexate, have their own set of side effects, which mayinclude reactivation of latent infections. Significant challengesremain in developing safe and efficacious novel targeted thera-pies that depend on a better understanding of the immunologicaldysfunction in psoriasis.

Keywords Psoriasis . Inflammatory response . Cytokines . Tcells . Dendritic cells . Biologics . Adverse effect

Introduction

Psoriasis, like most autoimmune diseases, is an immune-mediated dermatosis which is under the influence of geneticsand epigenetic modifications that can be triggered by environ-mental factors [1–3]. Psoriasis is a very common disease, af-fecting approximately 2 % of the world’s population [4].Psoriasis may present with variable clinical manifestations,and because of this and the lack of a biological marker ofdisease, may be difficult to diagnose. As a result, psoriasis isstill a clinical diagnosis which is defined by typical or atypicalmorphologic findings and appearances. The major clinicalmanifestations include characteristic skin lesions, includingplaques, and/or pustular or guttate lesions. But there are sev-eral clinical forms of psoriasis.

The most common type of psoriasis is psoriasis vulgaris,which accounts for nearly 85-90 % of all cases of psoriasis.Histologically, psoriasis is characterized by hyperproliferationand aberrant differentiation of keratinocytes, dilated, hyper-plastic blood vessels, and inflammatory infiltration of

* Qianjin Luepigenetics2010@126.com

1 Department of Dermatology, Second Xiangya Hospital, Hunan KeyLaboratory of Medical Epigenomics, Central South University,Changsha, Hunan, China

2 Division of Rheumatology, Allergy and Clinical Immunology,University of California at Davis, 451 Health Sciences Drive, Suite6510, Davis, CA 95616, USA

3 Second Xiangya Hospital, Central South University, #139 RenminMiddle Rd, Changsha, Hunan 410011, China

Clinic Rev Allerg Immunol (2016) 50:377–389DOI 10.1007/s12016-016-8535-x

378 Clinic Rev Allerg Immunol (2016) 50:377–389

leukocytes predominantly into dermis. The skin patches aretypically red, itchy, and scaly, which in addition to the phys-ical toll, may result in psychological stress and poor quality oflife. Like other systemic autoimmune diseases, psoriasis af-fects far more than the skin, and often presents with chronicinflammatory responses in joints, nails and other organs. Thecomplexity and prevalence of the disease taxes financial andhealthcare resources in many regions of the globe.

Immunological dysfunction in psoriasis involves the cross-talk between immune cells and cytokines. In the last 20 years,several important subsets of immune cells in psoriatic and otherautoimmune diseases have been identified to play a role inpathogenesis, including Th1, Th2, Treg [5], and Th17 cells.The corresponding cytokines that may be involved includeIFN-γ, TNF-α, IL-23, and IL-17. More recently, IL-9 secretingTh9 cells have been identified, and the inflammatory responsesof keratinocytes, γδT cells, T regulatory cells and other im-mune cell types in psoriasis have been explored. Evidence isemerging that new genetic variations and epigenetic modifica-tions are associated with psoriatic disease. Often these epige-netic modifications result from an environmental trigger.

There is currently no known cure for psoriasis. Treatmentgoals are related to controlling symptoms and reducing mor-bidity. Conventional therapies such as glucocorticosteroids,vitamin D derivatives, or combinations of both are only suffi-cient to manage mild disease. Research over the last decadehas demonstrated a changing treatment framework based onredefinition of disease severity and treatment goals, takinginto account the management of comorbid conditions andthe reduction of risk [6].

Pathophysiology

Complex genetics plays a role in psoriasis. The role of genet-ics has been studied using family and twin studies, lineagestudies, and genome-wide association studies (GWAS).Major histocompatibility complex (MHC), human leukocyteantigen C (HLA-C) and over 50 regions of susceptibility locihave been found to be associated with psoriasis [7–9].Genetics is only a part of the pathogenesis. Without the sim-ulation of certain environmental factors, epigenetic modifica-tion and inflammatory responses, people with high geneticsusceptibility may still fail to develop psoriasis, even thoughthey are at significantly higher risk.

Psoriasis can be provoked by non-specific triggers such astrauma (from scratching, piercing, and tattoos), chemical irri-tants or microbial infections [6]. Researchers have found thatStreptococcus infections can lead to T cell activation via theformation of superantigens [10, 11]. It has also been demon-strated that half of the Streptococcus cell wall-specific Th1cells in psoriatic lesions are specific for Streptococcus pepti-doglycan (PG), which is a strong pro-inflammatory stimulus

in chronic inflammation [12]. PG interacts with keratinocytes,dendritic cells (DCs) and monocytes via pattern recognitionreceptors (PRR) such as Toll-like receptor 2, nucleotide-binding oligomerization domains (NOD)-1 and 2 and PG rec-ognition proteins 1–4 in patients with psoriasis [13–15].Subsequently, active leukocytes, cytokines (Th1, Th2, Th17,Th22, CD8+T, and γδT cells), chemokines, adhesion mole-cules, growth factor, and subpopulations all act in an integrat-ed way to generate the inflammatory responses seen in psori-asis [16, 17]. Once triggered by external and/or internal stim-uli, activation of both the innate and adaptive immune systemoccurs, which result in the hyperproliferation and abnormaldifferentiation of keratinocytes, two of the critical contributorsto the underlying pathophysiologic dysregulation in psoriasis.

Genetics and Epigenetics in Psoriasis

Psoriasis is not inherited inMendelian fashion; however, thereis a familial predisposition [18]. A positive family historysignificantly increases the relative risk among first-degreeand second-degree relatives of patients compared to the gen-eral population [19]. Genetic studies have shown that HLA-Cw6 explains the largest part of the known heritability ofpsoriasis [20, 21]. GWAS have been successfully applied toexploration of the genetic architecture in psoriasis, andpsoriasis-susceptibility loci (PSORS1) has been confirmed tobe strongly associated with psoriasis, with an identification ofover 12 different PSORS loci from genetic analysis ofpsoriasis-affected families [22]. Collectively, the gene variantsrelevant to psoriasis can broadly be classified into two kinds:skin-specific and immune-specific genes [23].

Evidence for a Role of Genetics in Psoriasis

Firstly, single nucleotide polymorphisms (SNPs) and copynumber variation in genes of the late cornified envelope(LCE) family, which is involved in the epidermal cell and skinbarrier formation and is highly expressed in psoriatic lesions,highlight significant roles for skin-specific genes [24–26]. Theabsence of these skin-related genes, including LCE3B/3C, isfound significantly associated with a risk of psoriasis, whichhas been confirmed by two distinct studies frommultiple sam-ples from Spain (P=1.38E-08) and from Italy and the USA(p=5.4E-04), respectively [24].

Secondly, gene loci associated with psoriasis spans a seriesof functions mainly involved in adaptive immunity (antigenpresentation and IL-23/Th17 axis) and innate immunity(NF-κB) [27]. HLA-Cw6 that lies within PSORS1 and pos-sesses a highest odds ratio (OR) of nearly 3.0 compared withany other PSORS loci, encodes a major histocompatibilitycomplex I (MHCI) antigen which is well known to mediatedantigen presentation to CD8+ Tcells [28]. In addition to HLA-

Cw6, ERAP1 is a newly found susceptible gene related topsoriasis that has been demonstrated to occur in replicatedstudies from 9079 European samples. A recent study reportedthat ERAP1 takes part in MHCI peptide possessing byencoding an amino-peptidase which regulates the quality ofpeptides bound to MHCI molecules, just like HLA-C [29].

In addition, there is accumulating evidence supporting arole of genes in the IL-23/Th17 pathway to psoriasis throughGWAS [9, 26, 29, 30]. It has been identified that variants in ornear the genes IL-12B, IL-23R, and IL-23A are strongly as-sociated with psoriasis susceptibility [30, 31]. Interestingly,Paola et al. found that the IL23R R381Q gene variant doesnot directly inhibit activity of Th17 cells, but exerts a protec-tive effect through selective attenuation of IL-23-inducedTh17 cells, which is quite different from the former mutationsof IL-23R [32].

With respect to innate immunity, the NF-κB pathway is animportant transcription factor in the immune responses of al-most every immune cell type, and is regulated by alpha-induced protein 3 (TNFAIP3), TNFAIP3-interacting protein1 (TNIP1), v-rel reticuloendotheliosis viral oncogene homo-logue (REL), tyrosine kinase 2 (TYK2), and TRAF3-interacting protein 2 (TRAF3IP2) [33, 34]. Both TNIP1 andTNFAIP3 are genetically associated with several autoimmunediseases including psoriasis, SLE and RA [25, 35, 36].TNFAIP3 protein product inhibits NF-κB and it also workstogether with TNIP1 to prevent NF-κF-essential modulator(NEMO) polyubiquination and degrade the NF-κB inhibitor,causing hyperproliferation of keratinocytes, thus acceleratingthe development of psoriasis [37]. TRAF3IP2, identified as ashared susceptibility for both psoriasis vulgaris and psoriaticarthritis, encodes a protein involved in the IL-17 pathway andthe interplay with Rel/NF-κB transcription factor family [26,38]. Caspase recruitment domain-containing protein 14(CARD14), described as a causative gene at PSORS2, hasrecently been linked to psoriasis via activation of NF-κB. Itis striking to note that alterations in CARD14 result in anincreased production of inflammatory cytokines andchemokines in keratinocytes and endothelial cells by promot-ing NF-κB signaling [39, 40].

Epigenetic Regulation in Psoriasis

Although the critical role of heritability in psoriasis is difficultto refute, there is much that remains unexplained, and increas-ing data suggests an important role of epigenetic modifica-tions in driving psoriasis [41–43]. A genome-wide methyla-tion study from Han’s group demonstrated a hypomethylatedlevel of 26 regions of the human genome in psoriasis patientscompared to that of healthy controls. They further found thatthese regions are associated with histone modifications andtranscription factor binding sites in the coding region, suggest-ing that there is epigenetic regulation in psoriasis [44, 45].

Hypomethylated levels of SHP-1 and CpG in genes such asp15 and p21 have been observed in psoriasis patients [46, 47].In contrast, CpG methylation levels in genes of P16INK4a andP14ARF are abnormally elevated [47, 48]. In addition to ab-normal DNA methylation, histone modifications are also as-sociated with psoriasis. Global histone H4 hypoacetylation inperipheral blood mononuclear cells (PBMCs) is negativelycorrelated with disease activity as measured by psoriasis areaand severity index (PASI) score. Hyperproliferation ofkeratinocytes in psoriasis is due to decreased SIRT1 expres-sion [49].

MicroRNAs and long non-coding RNAs [50] are beingincreasingly found to play a role in autoimmunity, and a num-ber of miRNAs also contribute to the pathogenesis of psoria-sis. miR-203, the first skin-specific miRNA ever discovered,is overexpressed in psoriatic skin lesions by targeting suppres-sor of cytokine signaling-3 (SOCS-3) in the STAT3 pathway[51]. miR-210 expression is found to be increased significant-ly in CD4+T cells from patients with psoriasis by targeting offoxp3 [52]. There are many other miRNAs with aberrantlevels in psoriasis, including miR-221/222, miR-146, miR-125b, miR-99a and miR-31, which contribute to the regula-tion of keratinocyte proliferation [53–57].

Immunological Changes in Psoriasis

Psoriasis is characterized by keratinocyte over-proliferationand the abnormal infiltration of effector Tcells, dendritic cells,neutrophils and macrophages [58]. The effect of multiple celltypes involved in psoriasis is mediated by a complex networkof cytokines and their interactions.

The Role of Inflammatory Cytokines in Psoriasis

IFN-γ and TNF-α

IFN-γ and TNF-α act on keratinocytes and endothelial cells,leading to the activation, proliferation, and production of an-timicrobial peptides. It has been demonstrated that IFN-γ ismore relevant in the early stages of disease. IFN-γ induces thecross-phosphorylation of Janus kinase 1 (JAK2) and JAK3,which results in the downstream activation of STAT3. Thesubsequent activation of STAT factors is important for cellgrowth and is capable of regulating many genes expressed inpsoriatic skin lesions [59]. IFN-γ promotes the release of cy-tokines (IL23, IL-1), chemokines (CXCL10, CXCL11), andadhesion molecules from DCs [60]. Studies suggest thatIFN-γ may be useful as a biomarker for psoriasis diseaseactivity because of its positive correlation with PASI [61].

TNF-α not only regulates the antigen-presenting ability ofDCs but also promotes infiltration of T cells. This cytokineacts in part via phosphorylating NF-κB, the levels of which

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are elevated in psoriasis [62]. TNF-α also possesses pro-inflammatory properties and in psoriasis can facilitate IL-23production of DCs, suggesting that TNF-α acts as a regulatorof the IL-23/Th17 axis. For this reason, TNF-α inhibitors suchas etanercept serve their immune function partly by the sup-pression of IL-23, and by decreasing levels of Th17 effectormolecules, including IL-17, IL-22, chemokines and β-defensin [63]. Yuko et al. have observed that TNF-α directlytargets Th17 cells via attenuating autonomous TNF/TNFR2signaling in psoriasis [64]. Blocking of TNF-α signaling hasbeen more widely used in targeted biological therapy in pso-riasis, with biological modulators such as infliximab,adalimumab, golimumab, certolizumab, and onercept, all ofwhich have proven efficacy and relative safety in large, ran-domized, and controlled clinical trials [6, 65–69].

The IL-23/IL-17 Axis

IL-17 mRNA and protein levels are shown to be increased inthe blood or skin biopsies from human psoriasis lesions [70].IL-17 is primarily produced by Th17 cells, but recently, innateimmune cells, including γδT cells, neutrophils and mast cellshave been found to be involved in IL-17 secretion in psoriasis[71–73]. The IL-17 family includes at least six homodimericcytokines, IL-17A though IL-17F. IL-17A and IL-17F are themost relevant to psoriatic disease. IL-17 is widely touted as adirect potentiator in enhancing keratinocyte proliferation andinhibiting keratinocyte differentiation via the downstream me-diator REG3A, a protein with antimicrobial functions involvedin wound repair [74]. The previous data has demonstrated IL-17A stimulates the production of chemokines and antimicrobialpeptides by keratinocytes. Keratinocytes in turn promote Th17cell recruitment and produce more IL-17, resulting in a positivefeedback loop that perpetuates the inflammatory response ofpsoriasis [75, 76]. The role of IL-17 pathway has also beensupported by observations that AIN457, an antibody neutraliz-ing IL-17A, reduced PASI relative to baseline by 58 % whencompared to 4 % of placebo-treated psoriasis cases [77].

A phase 2 clinical trial of LY2439821, namely ixekizumab,showed a higher efficacy by suppressing expression of cyto-kines and chemokines involved in the IL-17 pathway [78].Conversely, IL-17 exhibits a protective influence on diseasedevelopment by suppressing TNF-α-induced CCL27 produc-tion through induction of COX-2 in human keratinocytes,which ultimately alleviates keratinocyte dysfunction in psori-asis [79]. In fact, IL-17 appears to be a two-edged sword and isinvolved in both immune defense and disease development ofmany autoimmune disorders, including psoriasis.

The increase of IL-17 and IL-17-secreting cells is closelyrelated to the altered balance between IL-23 and Th17 cells.IL-23 is pivotal in the survival and proliferation of Th17 cells[80]. IL-23 contributes to keratinocyte hyperproliferation and

thus facilitates the development of psoriasis. Both IL-23 andIL-12 belong to IL-12 family. The IL-12 P40 subunit is sharedby IL-12 and IL-23, which also have a unique submit, p35 andp19, respectively. DCs and macrophages are the main sourcesof IL-12 and IL-23, the levels of which are increased in pso-riasis skin. Emerging evidence has shown increased levels ofp19 and p40mRNA in lesional skin in contrast to non-lesionalskin, while there is no difference in p35 levels [81]. In otherwords, it is IL-23 but not IL-12 that drives the pathogenesis ofpsoriasis. IL-23 protein levels in psoriatic skin lesions are alsomuch higher compared to that in non-lesional skin [82]. All ofthe above information and single nucleotide polymorphismstudies support the observation that IL-23 is a critical cytokinein disease pathogenesis [30, 83].

IL-22

IL-22, originating from Th17 and Th22 cells, induces IL-23-mediated keratinocyte hyperproliferation in vivo and in vitro,through STAT3 signaling [84]. Elevated levels of IL-22 arefound in the blood of psoriatic patients [85], and IL-22 exertsits effects in tissues by binding to its heterodimeric receptor,consisting of the IL-10 receptor B and IL-22RA, which are ex-clusively expressed on epithelial cells such as keratinocytes inthe skin [86]. The combination of IL-22 and IL-17 inhibits thedifferentiation of keratinocytes and increases their proliferationand mobility, which leads to retention of nuclei in the stratumcorneum (parakeratosis), epidermal hyperplasia (acanthosis), andelongation of the epidermal rete ridges (papillomatosis), whichare the hallmarks of skin psoriatic plaques [87].

IL-9

IL-9 expression in lesional skin from psoriasis patients wasfound to be markedly higher than that in healthy skin from thecontrol subjects. Singh et al. and his group have demonstratedincreased IL-9R and IL-9 expression in the skin and inductionof a Th17-related inflammatory response after intradermal IL-9 injection in a psoriatic mouse model [88]. IL-9 is a pro-inflammatory cytokine that promotes secretion of IL-17, IL-13, IFN-γ and TNF-α in psoriasis. Both Th9 and Th17 cellsare sources of IL-9. In another autoimmune disease model,anti-IL-9 monoclonal antibody not only blocks IL-9 signalingbut also weakens Th17 function by suppressing IL-17 expres-sion, suggesting that IL-9 may work as a mediator or target forinhibition of the IL-23/Th17 pathway [89, 90]. Additionally, asusceptibility gene for psoriasis is located on chromosome5q31.1-q33.1, close to the location of the IL-9 gene [91].The exact mechanisms by which these cytokines regulate themicroenvironment of psoriasis still require further research.

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Inflammatory Roles of T Cells in Psoriasis

Th1 and Th2 Cells

Th1 cells were originally considered to be the main mediator ofthe immune response in psoriatic plaques [92, 93]. Increasedexpression of both mRNA and protein levels of IFN-g, TNF-α,and IL-12, but not IL-4, IL-5, or IL-10 have been documentedin some studies [94–96]. On the other hand, Armanda et al.found that IL-4 ameliorated disease not only via promoting Th2polarization, but also via direct inhibition of inflammatory cy-tokines in epidermal cells. This was supported by the observa-tion that IL-4 leads to upregulation of epidermal GATA3mRNA and protein in psoriatic skin and inhibition of IL-1βand IL-6 via transcriptional and post-transcriptional mecha-nisms [97]. IL-1β plays an important role in upregulating IL-6, IL-8, TNF-α, and hBD2 expression, differentiation of Th17and Th22 cells, and stimulation of IL-17 and IL-22 secretion[98–100]. Thus by suppressing this pathway, the Th2 cytokineIL-4 is able to restore psoriatic skin to a healthy phenotype.

It has also been reported that genes encoding for Th1 cyto-kines but not Th2 are overexpressed in mesenchymal stem cells(MSCs) from psoriasis cases compared with healthy controls.This reflects an imbalance between the Th1 and Th2 paradigms[101]. There appears to be a bidirectional response pattern ofTh1/Th2 balance, with a various skewing in different forms ofpsoriasis, when measuring specific cytokines and ratios of Th1/Th2 cells. In one of the most serious forms of psoriasis,erythrodermic psoriasis (EP), there is a higher expression ofTh2 cytokines (IL-4, IL-10) than in the more commonly seenpsoriasis vulgaris (PV). The Th1/Th2 ratio of EP is dramatical-ly lower than in PV sufferers (P<0.01) [102]. It appears thatthe pathogenesis of psoriasis somehow involves the immuneresponses of both Th1 and Th2 cells; although, how the balanceof Th1/Th2 skewing leads to psoriasis is not fully known.

What is known is that Th1 cells and IFN-γ levels are in-creased in psoriasis and lesional skin. Interferon-γ activatesantigen-presenting cells early in the psoriatic cascade [103],and has been found to stimulate APC production of CCL20.CCL20, support migration of IL-17+T cells, and also synergizewith IL-17 in the production of β-defensin2 (HBD-2), an anti-microbial and chemotactic protein highly overexpressed by pso-riatic keratinocytes [103]. Under the influence of Th1 cells, dys-regulated keratinocytes release a rich source of AMP and IL-1family cytokines including IL-1β and IL-18, which are furtherinvolved in the differentiation of Th1 and Th17 cells, respective-ly [104, 105]. This suggests that Th1 cells participate in thepathogenesis of psoriasis in conjunction with Th17 cells [106].

Th17 Cells

Th17 differentiation is dependent on the transcription factorRORγt, and the coexistence of IL-1β, TGF-β, IL-6 and IL-23

[107, 108]. Evidence is accumulating that effector T cells con-tribute to psoriasis immunopathogenesis, in which the Th17subset is of central importance, in both human and mousemodels. On the one hand, the number of IL-17-producingCD4+T cell has been observed to be much higher in psoriaticskin lesions than in healthy skin [109, 110]. Th17 cells arecrucial for secretion of IL-17, IL-12, IL-22, and IL-9, all ofwhich directly or indirectly promote the inflammatory re-sponse of keratinocytes. Furthermore, antimicrobial peptides,cytokines and chemokines such as CCL20 and CXCL1, 3, 8–11 secreted by keratinocytes, act as chemoattractants to am-plify the immune response in psoriasis [111–113]. In turn,activated Th17 cells enhance the inflammatory response ofkeratinocytes, creating a positive feedback loop around theIL-23/Th17 axis.

Recent murine studies also suggest that the Th17 pathway isessential to the pathogenesis of psoriasis. Topical imiquimod(IMD) may induce psoriasiform skin inflammation in mousemodels, which is primarily mediated through the IL-23/Th-17axis [114]. Blocking of this axis using anti-IL-23 antibodies hasshowed great promise in suppressing the development of psori-atic diseases [115]. Neutralization of IL-22 using antibody orknockout mice inhibited IL-23-induced skin thickening [116].Dysregulated of IL-17 signaling and Th17 cell pathway functionthus promotes chronic inflammation in psoriasis. Reversing thisdysfunction is the focus of current clinical trials in psoriasis.

Regulatory T Cells

Polarization of regulatory T (Treg) cells is primarily regulatedby a combination of TGF-β, IL-4, IFN-γ, IL-2, and IL-6, aswell as other T cell populations [117]. Mature Treg cells ex-press Foxp3, TGF-β, IL-10, perforin, and granzyme A. Tregcells help maintain peripheral tolerance, thus limiting chronicinflammatory diseases and preventing autoimmune diseases[118–120]. Treg cells play important roles in maintaining ho-meostasis and may cause local suppression of other immunecells, including Th17 cells. IL-6, which is required for thedifferentiation of Treg cells, hampers the activation and pro-liferation of Th17 cells [121, 122]. Hence, it induces a balancebetween Tregs and Th17 cells. It has been shown that in-creased Treg cell counts may be seen in the skin lesions ofpsoriasis patients [123]. Treg cells usually suppress otherpathogenic T cells like Th1 and Th17 cells in psoriasis.Dysfunction of Tregs by CD18 knockout allows thehyperproliferation of pathogenic T cells in psoriasis models.In the Cd18hypo PL/J mouse model, reduced CD18 expressionresulted in impaired function and low proliferation of Tregcell, with 51.5 % gated CD4+CD25+CD127− Tregs by flowcytometry, compared to a much higher rate of 81.9 % in thewild type (Cd18wt). The dysfunction of Treg cells can be re-versed by adoptive transfer of Cd18wt Tregs into Cd18hypo PL/J mouse, resulting in an improvement of the psoriasis [124].

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Similar to this, ameliorated psoriasis-like skin lesions andlower Th17 cytokines but increased numbers of Treg cellsare observed recently in IMQ-induced mice after combinedtreatment of glucosamine and low-dose cyclosporine [125].Another study showed that CD4+CD25+ T cells differentiatedin vitro from hematopoietic cells of patients with psoriasis areimpaired in their regulatory capabilities [126].

γδT Cells, Th22 Cells, and Th9 Cells

A close relationship has been showed between psoriasis andother immune cells including newly identified IL-9-producingCD4+T cells and IL-17 producing γδ T cells [88, 127]. γδT,Th22, and Th9 cells have been recently identified to play rolesin the pathogenesis of psoriasis, with their main effector cyto-kines being IL17, IL-22, and IL-9, respectively, thus amplify-ing the function of the Th17 pathway in psoriasis. γδT cellsproduce IL-17 and promote a Th17 inflammatory responseafter their rapid activation by IL-23, IL-1β, or danger signals[128]. It has been established that epidermal hyperplasia andinflammation, along with IL-17 levels, are significantly de-creased in T cell receptor δ-deficient (Tcrd−/−) mice[129–131]. In addition, IL-23-induced or IMQ-induced skininflammation and acanthosis are observed only in wild-type(WT) mice rather than Tcrd−/− mice, suggesting that γδT cellsare necessary for the development of psoriasis [114, 129]. Inhuman studies, Cai et al. also found large numbers of IL-17-secreting γδTcells in lesions from patients with psoriasis, anddermal γδT cells are a significant source of IL-17 and CCR6upon IL-23 stimulation in the skin [129].

Human γδT cells from blood are usually Vγ9Vδ2 T cells,which are increased in skin but decreased in the peripheralblood in psoriasis patients, suggesting that γδTcells redistrib-ute from blood toward the skin in order to participate in thepathogenesis of psoriasis. Vγ9Vδ2 T cells release largeamounts of psoriasis-relevant cytokines IFN-γ, TNF-α, andIL-9 and pro-inflammatory chemokines, CCL3, CCL4, andCCL5, confirming their important role in the pathogenesis ofpsoriasis [132].

IL-22-producing Th22 cells and IL-9-producing Th9 cellsmake up other two distinct subsets of effector T cells. IL-22can lead to induction of cytokine-specific chemokines andaugmentation of specific effector responses mediated by theIL-23/Th17 axis [133]. IL-9 works as a potent mediator ofTh17 cell signaling. Studies of γδT, Th22, and Th9 cells inpsoriasis, although still in their infancy, are expected to be agrowing interest in the study of potential mechanisms of in-flammatory responses and pathogenesis of psoriatic disease.

CD8+T Cells

The PSORS1 gene lies within the class I region of the MHC.CD8+ Tcells in the blood of psoriasis patients frequently carry

the HLA-Cw6 allele, the most important susceptibility locithat has ever been found in psoriasis [134]. Johnston et al.found that CD8+T cells recognized keratin self-antigens,which along with epitopes shared by StreptococcalMproteinswere the target of CD8+T cells in infiltrating psoriatic skinlesions [135]. In addition, the observation that perforin-mediated cytotoxicity of CD8+T cells caused keratinocytedamage in psoriasis further strengthens the importance ofCD8+T cell in the disease pathogenesis [136]. In other words,apoptotic keratinocytes induced by CD8+T cells initiate a vi-cious cycle of regenerative hyperplasia of epidermalkeratinocytes, thereby promoting the development ofpsoriasis.

Other Immune Cell Types With a Role in Psoriasis

There are many other immunocytes that also exert inflamma-tory effects in psoriasis, notably dendritic cells (DCs) [137],natural killer (NKs) cells, and macrophages. In a broad sense,there are three types of dermal resident DCs: (1) epidermalLangerhans cells (LCs), (2) dermal myeloid DCs (mDCs), and(3) plasmacytoid DCs (pDCs) [138, 139]. Nestle et al. werethe first to find the close relationship between DCs and psori-asis. They observed that in psoriasis plaques, skin-derivedDCs mediate higher levels of IL-2 and IFN-γ production thanDCs in healthy skin [140]. Additionally, compared to normalskin, there is an increased number of pDCs in psoriatic skinlesions (up to 16 % of the total dermal infiltrate) triggered bythe Toll-Like Receptor (TLR) 7 agonist IMD [141].

Studies have identified that IFN-α signaling mediated bypDC is an initiator of psoriatic inflammation [142]. IFN-αproduced by pDCs induces a upregulation of IL-17 and IL-23, which also polarizes Th17 cell differentiation and poten-tiates IL-17 production [143]. Lowes et al. found high levelsof TNF-α and iNOS producing DC subsets in human psoria-sis. Blockade of TNF-α using etanercept induced disease im-provement in psoriasis [144, 145]. Similarly, CD11c+DC cellcounts were increased in psoriasis lesions and reduced afterclinical response induced by efalizumab, alefacept, infliximaband NB-UVB [133].

Natural killer (NK) cells are a distinct subset ofCD56+CD16+ cells which are well known for their ability tokill virally infected and cancer cells [146]. Studies fromOttaviani et al. have suggested that NKs are capable of pro-ducing large quantities of IFN-γ, inducing activation ofkeratinocytes and upregulation of MHC class I molecules[111]. More importantly, activated keratinocytes were ob-served to attract NK cells by secreting chemokines such asCXCL10, CCL5, and CCL20 [111].

In addition to DCs and NK cells, there is mounting evi-dence that neutrophils and macrophages may contribute topsoriasis. Neutrophils recruited by chemokines CXCL1,CXCL2, and IL-18 contribute to the recruitment of activated

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effector Tcells. Moreover neutrophils also produce AMPs andIL-17 in psoriasis patients [147, 148]. Infiltration of macro-phages promotes keratinocyte proliferation and the develop-ment of psoriasis. In fact, cutaneousmacrophages can producemany inflammatory mediators and cytokines, one of which isIL-23, a crucial participant in the pathogenesis of psoriasis[149] (Fig. 1).

Treatment and Management

Traditional Therapy

Conventional treatment of psoriasis mainly includes corticoste-roids, Vitamin D analogues, phototherapy and systemic treat-ments [150]. The lack of biomarkers presents an additional road-block to optimizing treatment [151]. Topical glucocorticosteroidsand Vitamin D analogues, both of which regulate keratinocytefunction and the inflammatory response, are usually sufficient totreat mild disease. Nevertheless, continuous corticosteroid use isassociated with some risks [152] including loss of efficacy, cu-taneous atrophy and rebound or pustular psoriasis. Vitamin Danalogues fail to have a fast onset of activation, although they donot possess the more severe side effects of corticosteroid [153].In the case of moderate-to-severe psoriasis, ultraviolet B light incombination with systemic drugs such as methotrexate is still anacceptable therapy, especially for those patients with arthritis ornail involvements. Methotrexate is widely used because of itsreasonable price and high efficacy over protracted periods, andmore than 75 % of patients acquire 50 % reduction in diseaseseverity [154–156]. Nevertheless, the adverse effects that

patients may suffer are potentially very serious, and include liverfibrosis and cirrhosis.

Biological Modulators

Biological modulators targeting molecules involved in thepathogenesis of have been developed over the past 2 decades[157]. Biological therapies are usually advocated when tradi-tional treatments have failed, are contraindicated or lead tosevere adverse effects [158]. This is partially due to the highcost of biologicals. Generally, these newer treatments are cate-gorized into several broad groups: TNF-α inhibitors(etanercept, adalimumab, infliximab, golimumab, certolizumaband onercept), IL-12/IL-23 inhibitors (ustekinumab), IL-17 in-hibitors (secukinumab), inhibitors of T cell activation and sig-naling (alefacept), and others. Among the biologics, etanerceptis FDA approved for moderate-to-severe chronic plaque psori-asis, with a dosing regimen of 50mg twice a week for 3monthsfollowed by a maintenance dose of 50 mg per week [159, 160].Comparison of improvements in PASI between etanercept andmethotrexate showed no statistical difference over a 2-weektreatment period. However, patients treated with etanercepthad higher remission of arthritis and erythra than methotrexateafter 6 weeks, suggesting that etanercept may be a better choicefor maintenance in the long run (P<0.05).

In addition, combination therapy with etanercept plusmethotrexate had acceptable tolerability and PASI 75 im-provement compared with etanercept monotherapy in a 24-week treatment (77.3 vs. 60.3 %, P<0.001) [161]. With re-gard to other biological modulators, the TNF-α inhibitorgolomumab is approved for psoriatic arthritis, and the

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Fig. 1 Inflammatory cytokinesignaling and effector immunecells in the pathogenesis ofpsoriasis: Th1/Th2 proportion,Th17/Treg balance and IL-23/Th17 axis are particularlyimportant in psoriasis

IL12/IL-23 inhibitor ustekinumab is acceptable both in psori-asis and psoriatic arthritis. Numerous other biologics, whichspan an array of functions involved in blocking the JAK fam-ily of kinases (tofacitinib), correction of cytokine deviation(IL-10), and inhibiting phosphodiesterase-4 (apremilast) arein advanced phases of clinical trials [162, 163]. Each biolog-ical modulator acts on the immune system in a different way,but due to the redundancy of the immune system and geneticvariation, none work equally well for every patient.

Adverse Effects

Compared to conventional treatments, biologics provideshigher efficacy and sometimes better safety profiles, but havebeen found to possess new and unexpected adverse effects[164]. Blockade of Th17 and TNF-α induces the downstreaminhibition of IL-17, IL-12, IL-23, and TNF-α itself, impairingimmunity to fight against intracellular bacteria and granulo-matous infections. Hence, TNF-α inhibitors may lead to reac-tivation of tuberculosis, while an impaired IL-23/Th17 path-way is closely associated with risk of salmonella infection,tuberculosis and mycobacterial disease [165–168]. A currentstudy has estimated the different degrees of susceptibility toinfection among common biologics in clinical treatment. Inthe infliximab cohort, there is cumulative incidence rate ofinfection of 2.49 %, which is much higher than the rates inustekinumab (0.83 %), etanercept (1.47 %), and adalimumab(1.97 %). Indeed, infliximab exposure associated with otherrisk factors including increasing age, diabetes mellitus,smoking, and significant infection history led to a higher sus-ceptibility to serious infection [169].

Followed by infection, cardiovascular disorders have beenreported to occur with the use of the newer biologics. TNF-α

inhibitors have been reported to be a potential cause of cardio-vascular events. However, other meta-analysis showed con-flicting observations in that only 1 of 3858 patients receivingTNF-α inhibitors experienced major adverse cardiovascularevents (MACE) compared with 1 to 1812 patients receivingplacebo (P=0.12), suggesting that there was no significantdifference in the rate of MACE after TNF-α inhibitor treat-ment [170, 171]. The same observations can be made withregard to IL12/IL23 antibodies. The differences between thesestudies may be reflected by different patient populations andthe statistical methods used, and the actual role of biologics inMACE still needs to be further investigated.

In addition, comorbidities such as nausea, diarrhea,nasopharyngitis, and headache may occur with biologics[172, 173]. IL-17 inhibitors may block the anti-tumor effectwhich is mediated by IFN-γ and the anti-angiogenic effect ofIL-17F, thus increasing the risk of malignancy in psoriasispatients [172]. Biologics are also much more expensive andthe response is variable with only one third of psoriasis pa-tients experiencing significant improvement [174]. At present,we are still far from finding a cure for psoriasis, but what wedo know is that it is an incredibly complex autoimmune dis-ease that will require a better understanding of its pathogenesisin order to develop new treatment modalities (Table 1).

Conclusion

Psoriasis is more than just a Th1 type disease, and accumulat-ing evidence is available to demonstrate the crucial roles ofeffector cell subsets including Th17, Th22, Th2, Treg, CD8+Tcells, and other immune cells such as DCs, NKs cells, macro-phages in the pathogenesis of psoriasis. Among the

Table 1 Summery of anti-psoriatic therapies

Drug Mechanism of action Efficacy Common deficiency Reference

Glucocorticosteroids Inhibition of inflammatory reactions,DNA synthesis, vasoconstriction,and immunosuppression

++++ Skin atrophy [164]

Vitamin D analogues +++ Low onset of activation, mild discomfort [164]

Phototherapy (UVB, UVA) Inhibiting epidermal hyperproliferation +++ Skin premature aging, skin cancer [164]

Methotrexate Immunosuppression + to ++ Liver fibrosis [164]

Cyclosporine Immunosuppression ++ to +++ Hypertension, malignancy, infection [164]

Etanercept Blocking TNF-α pathway + to +++ Infection, malignancy [164, 169]

Infliximab Blocking TNF-α pathway +++ to ++++ Infection, [169]

Adalimumab Blocking TNF-α pathway +++ Infection, lupus-like syndrome, malignancy [164, 169]

Ustekinumab Blocking IL-12/IL-23 signaling +++ Infection [164]

Secukinumab Blocking IL-17 signaling Not indicated Nasopharyngitis, headache [173]

Global assessment: there are six levels for estimating efficacy

Poor——————————————————————Good

− +/− + ++ +++ ++++

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mechanisms involved in psoriasis, Th1/Th2 proportion,Th17/Treg balance, and IL-23/Th17 axis appear to be partic-ularly important. Recently, IL-9-producing Th9 cells and IL-17-producing γδT cells have been found to play significantroles in the pathogenesis. New discoveries in the pathogenesisof psoriasis have already led to novel treatment modalities[175]. Further research in individual gene susceptibility andthe role of environmental triggers and epigenetic modifica-tions are needed to address the unmet need of personalizedmedicine in the treatment of autoimmune diseases such aspsoriasis [176, 177].

Acknowledgments This work was supported by grants from theNational Natural Science Foundation of China (Nos. 81220108017,81430074, 81270024, and 30972745).

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