The Association of Psoriasis and Obesity:Focusing on IL-17A-Related Immunological Mechanisms

Cheng Xu,Jie Ji,Ting Su,Hong-Wei Wang,Zhong-Lan Su,*

1Department of Dermatology,The First Affiliated Hospital of Nanjing Medical University,Nanjing,Jiangsu 210029,China,2State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine,Medical School,Nanjing University,Nanjing,Jiangsu 210093,China.

Abstract Psoriasis is a chronic,recurrent,inflammatory skin disease that is often accompanied by obesity.An increasing amount of research has elucidated the pathophysiological link between psoriasis and obesity.Since 2005,interleukin(IL)-17-producing T helper 17 cells and their main effector cytokine IL-17A have been considered to play a critical role in the pathogenesis of psoriasis;the marked effect of biotherapies targeting IL-17A on moderate and severe psoriasis has further established its role in psoriasis.Recent studies have found that obesity induces T helper 17 cells to secrete IL-17A and participate in the pathogenesis of psoriasis.IL-17A may be a crucial element in the association between psoriasis and obesity.This review discusses the association between psoriasis and obesity,with a focus on and the implications regarding the need to treat psoriasis.

Keywords:interleukin-17A,obesity,psoriasis

Introduction

Psoriasis is a chronic inflammatory disease caused by complex interplay between the immune system,polygenic inheritance,and environmental factors.The estimated worldwide prevalence of psoriasis is 812/100,000 personyears.1In the past 10 years,the interleukin(IL)-23/17 pathway has been identified as the key axis in the pathogenesis of psoriasis.The primary effector of this pathway is IL-17A,and overexpression of IL-17A leads to epidermal hyperplasia and strong inflammation,resulting in the skin plaques and systemic inflammatory response seen in psoriasis.Targeted anti-IL-17 therapies have demonstrated efficacy in the treatment of moderate-tosevere plaque psoriasis.2

A recent study has showed that obesity is a common complication of psoriasis.2Furthermore,evidence suggests that psoriasis and obesity may have a common chronic inflammation course.3Obesity promotes the development and deterioration of psoriasis through the pro-inflammatory pathway and has a significant effect on the therapeutic response of patients with psoriasis.A recent study has found that IL-17A also plays an important role in the pathogenesis of obesity.Obesity promotes an expansion of the T helper 17(Th17)T-cell sublineage in an IL-6-dependent process,thus increasing the secretion of IL-17A to participate in the pathogenesis of psoriasis.4We searched PubMed by using search strategies(psoriasis*[MeSH Major Topic])AND(obesity[MeSH Major Topic]OR(interleukin-17A*[MeSH Subheading])from 2008.1 to 2019.9,to collect relevant literature for this article.In this review,we tend to explain the vital role of IL-17A in mediating the common inflammatory environment of psoriasis and obesity,which has the latent directive significance to the treatment of psoriasis.

IL-17A:cellular sources,receptor,and biological functions

The IL-17 family ofcytokines is composed of six members of varying homologyand function:IL-17A,IL-17B,IL-17C,IL-17D,IL-17E,andIL-17F.IL-17A is a proinflammatory cytokine mainly secreted by Th17 cells,CD8+cytotoxic T cells,gamma delta T cells(γδT cells),lymphoid tissue inducer-like cells,CD3+invariant natural killer T cells,and natural killer cells.However,macrophages,mast cells,and neutrophils are additional sources of IL-17A.5The IL-17 cytokines act as homodimers or heterodimers and interact with a group of transmembrane receptors called the IL-17 receptor family.IL-17R consists of five subunits termed IL-17RA to IL-17RE,which are widely expressed in hematopoietic and non-hematopoietic cells.5IL-17A signaling transduction requires the formation of a heterotrimeric receptor complex comprising IL-17RA and IL-17RC,leading to the activation of nuclear factorκB(NF-κB)and mitogen-activated protein kinase(MAPK)pathways,which further inducing the production of various inflammatory cytokines such as IL-6 and tumor necrosis factor(TNF)-α.These inflammatory cytokines also trigger the abovementioned signaling pathways,resulting in a continuous cycle of inflammation.6Recent research has demonstrated that IL-17RD constitutes a second functional receptor for IL-17A,and mediates the proinflammatory gene expression downstream of IL-17A together with IL-17RC.7IL-17 is a potent inducer of inflammatory cytokines,chemokines,matrix metalloproteinases,and antimicrobial peptides,and recruits neutrophils and monocytes to the site of inflammation.8IL-17 functions at mucosal and barrier sites to protect the host from bacterial and fungal infections,and plays a critical role in maintaining the homeostasis between host and microorganisms.However,once the homeostasis is disrupted,IL-17 promotes the occurrence of autoimmune or autoinflammatory diseases.Furthermore,accumulating evidence indicates that IL-17 not only promotes tumorigenesis but also exerts antitumor functions.5

Role of IL-17A in psoriasis

The IL-23/17 inflammatory axis plays an important role in the pathogenesis of psoriasis.9Naive T cells activate signal transducer and activator of transcription 3(STAT3)to induce the expression of retinoic acid-related orphan receptorγt(RORγt)under the synergistic effect of transforming growth factor(TGF)-βand IL-6,thus promoting the differentiation of naive CD4+T cells into Th17 cells and upregulating the expression of IL-23 receptors.The IL-23 secreted by dendritic cells(DCs)and macrophages binds these receptors to activate Th17 cells and induce the production of IL-17A,IL-22,IL-21,interferon(IFN)-γ,and TNF-α.10These cytokines accelerate keratinocyte proliferation and inflammatory cell recruitment,and sustain skin inflammation.Another important source of IL-17A in psoriasis areγδT cells,which express the transcription factor RORγt and the signature cytokine receptor IL-23R.After leaving the thymus,γδT cells begin to rapidly produce IL-17A via peripheral stimulation with IL-1βand IL-23,independent of T cell receptor stimulation.11IL-17A plays a very important role in maintaining the inflammation of psoriasis.The expression of IL-17A is higher in the serum and plaque scales of psoriatic patients than in healthy people,and there is a significant positive correlation between the concentrations of IL-17 in serum and scales and the severity of psoriasis.12Keratinocytes are the main target of IL-17A in psoriasis.The binding of IL-17A homodimers and IL-17RA/IL-17RC or IL-17RA/IL-17RD heterodimers activates various signal transduction molecules in keratinocytes.Aside from MAPK and NF-κB,STAT3 also plays an essential role in the development of psoriasis.The activation of STAT3 promotes keratinocyte proliferation and an inflammatory response.13IL-17A downregulates the expression of filaggrin and genes important for cellular adhesion,which may affect epidermal barrier formation.14IL-17A also accelerates the excessive proliferation and abnormal differentiation of epidermal keratinocytes.15Moreover,IL-17A upregulates various cytokines(IL-8),chemokines(CXCL-1,CXCL-3,CXCL-5,and CXCL-6)and antimicrobial peptides(β-defensin)related to psoriasis and upregulates the direct recruitment of immune cells(including chemotactic neutrophils and Th17 cells)to the skin,thereby establishing a feedback loop that maintains inflammatory cells in lesional skin.16IL-17A also stimulates DCs and fibroblasts to produce IL-6,and promotes the differentiation of T cells into the Th17 phenotype.Furthermore,IL-17A promotes the proliferation and angiogenesis of endothelial cells by stimulating fibroblasts to produce vascular endothelial growth factor.17Finally,IL-17A stimulates macrophages and DCs to produce IL-1 and TNF-αto participate in the inflammatory environment of psoriasis.18

To date,three biologic agents that target the IL-17 signaling pathway have been approved for the treatment of moderate to severe plaque psoriasis in adults.Secukinumab and ixekizumab are monoclonal antibodies against IL-17A,whereas brodalumab is a fully human monoclonal antibody against IL-17RA.Numerous randomized trials have shown that all IL-17 inhibitors effectively alleviate the skin lesions of patients with moderate to severe plaque psoriasis.The incidence of psoriasis area and severity index(PASI)75 remission was significantly higher in the group receiving IL-17 inhibitors(75%-90%)than in the placebo group.15-16Moreover,a large proportion of patients achieved PASI 90 and PASI 100,which showed the excellent efficacy,tolerance,and safety of IL-17 inhibitors,and greatly changed the psoriasis clinical treatment protocol.19

Role of IL-17A in obesity

Obesity is a condition that involves chronic and subclinical inflammation.Visceral AT is the largest endocrine organ.In addition to storing fat,AT also plays an important role in the integration of endocrine,metabolic,and inflammatory signals.When people are storing excess fat,AT expansion is accompanied by severe infiltration of neutrophils,B cells,T cells,DCs,macrophages,and other immune cells.These infiltrating cells are responsible for the development of inflammation in AT and produce proinflammatory cytokines(TNF-α,IL-6,IL-8,IL-17A,IL-18,and monocyte chemoattractant protein-1)and adipokines(resistin,visfatin,and retinol-binding protein 4).20The cytokines and adipokines produce a marked effect by generating free radicals to promote the synthesis of reactive oxygen species and induce oxidative stress,which triggers the activation of NF-κB,p38 MAPK,extracellular signal-regulated kinase-1/2,and Jun N-terminal Kinase(JNK)transcription factors and enhances the expression of proinflammatory cytokines,thus amplifying the local inflammatory responses.21As a proinflammatory cytokine,IL-17A is equally important in the pathogenesis of obesity.The plasma concentrations of IL-17 and IL-23 are increased in women with obesity.22Furthermore,in an animal model of zymosan-induced peritonitis in ob/ob mice with genetic leptin deficiency and those with dietinduced obesity,neutrophils produce the majority of proinflammatory IL-17A,which is related to an increased concentration of IL-6,but not IL-23 or IFN-γ.23Another animal study reported an increased basal level of IL-17A,p-STAT3,and p-extracellular signal-regulated kinase in the subcutaneous AT of obese mice.24Overall,these findings suggest that IL-17A differentially activates signaling pathways and induces inflammatory and metabolic gene expression in the AT of lean and obese mice.

Obesity induces the differentiation of Th17 cells,and IL-17A is a crucial link in this immune response.The latent effect of the IL-23 pathway in obesity has been investigated.The level of DCs with an immature phenotype derived from AT(ATDCs)is increased in obese mice.These ATDCs seem to secrete higher levels of IL-6,TGF-β,and IL-23 than DCs derived from the spleen;furthermore,ATDCs have higher mRNA levels of IL-23p19 and IL-12/IL-23p40,but not IL-12p35.These findings suggest that ATDCs promote Th17 cell differentiation mediated by IL-23 and other cytokines in AT.25Patients with obesity have increased expression of TNF-α,which induces the differentiation of monocytes into mature DCs,and indirectly promotes the differentiation of naive T cells into Th1 and Th17 cells.26Furthermore,patients with obesity have increased levels of IL-6,which is mainly produced by adipocytes and macrophages in visceral AT.The overexpression of IL-6 activates intracellular STAT3 and RORγt to differentiate the Th17 cell lines to secrete IL-17A under the synergistic effect of TGF-β.This is a positive feedback mechanism,as IL-17 stimulates the production of IL-6.AT-derived stem cells obtained from patients with obesity promote Th17 cell differentiation by increasing the transcription of IL-17A through activation of the PI3K and STAT3 pathways.Moreover,signals derived from AT-derived stem cells induce inflammasome activation and IL-1βsecretion by monocytes,and this secreted IL-1βis required to maintain or further increase IL-17A production by Th17 cells.As a result,chronic low-grade inflammation develops in patients with obesity.27An increased concentration of serum amyloid A in obesity-related inflammation stimulates the differentiation of Th17 cell lines by means of increased IL-23 production by DCs.28Recent studies have also found that obesity induced by a high-fat diet promotes the development of Th17 cells and the expression of enzymes related to fat metabolism,including acetyl-CoA carboxylase 1.29Acetyl-CoA carboxylase 1 aggravates the inflammatory reaction mediated by IL-17A.γδT cells bridge the innate and adaptive immune inflammatory responses.In the periphery,γδT cells are naturally and rapidly activated to secrete cytokines,such as IFN-γ,TNFα,and IL-17A.Recent research has shown thatγδT cells are also present in AT,although the role ofγδT cells in the obesity-inflammation cycle remains unclarified.30As IL-17A receptor is widely expressed,IL-17A plays an important role in the inflammatory diffusion of obesity.IL-17A inhibits the differentiation of adipocytes and stimulates lipolysis in adipocytes,while also playing a protective role in fat metabolism by inhibiting adipogenesis.31These findings show that IL-17A is of great significance in the regulation of inflammation and lipid homeostasis in obesity.

Relationship between psoriasis and obesity and its relevance to treatment based on Il-17A role

Many epidemiological studies have confirmed the association between obesity and psoriasis.A prospective study involving 892 patients with psoriasis showed that obesity is a risk factor for disease development and may precede psoriasis.32The prevalence of obesity is higher in psoriatic patients than in the general population.Furthermore,the BMI of psoriatic patients tends to increase over time.

The relationship between psoriasis and obesity may involve multiple mechanisms,including a common chronic inflammatory state and overlapping genetic background and environmental factors.Many cytokines produced in the chronic inflammatory state of psoriasis,such as TNF-α and IL-6,induce insulin resistance to promote obesity through various mechanisms.33Compared with the general population,psoriatic patients have higher risks of social isolation,poor eating habits,depression,reduced exercise,and alcohol consumption,all of which promote obesity.33The administration of some systemic drugs used to treat psoriasis may also indirectly lead to obesity.For example,TNF-αantagonist therapy may be related to weight gain in patients with psoriasis.34

Genome-wide association studies have identified many susceptible genes related to the pathogenesis of psoriasis,including HLA-Cw6.The risk of psoriasis is approximately 35 times greater in patients with obesity with HLACw6+compared with lean people with HLA-Cw6-,indicating that the susceptibility genes of psoriasis are strongly correlated with obesity.35Psoriasis patients homozygous for the FTO rs9930506 G allele have a higher BMI,high risk of obesity,and potentially increased risk of arthritis.36IL-17-related genes have also been identified in recent years.36Kaur et al.37speculated that the polymorphism of IL-17A leads to its increased expression,thereby affecting the susceptibility and severity of psoriasis.In addition,IL-17A upregulates the expression of various inflammatory genes in the target tissue,further inducing the production of chemokines,cytokines,and other inflammatory mediators.IL-17A also plays an important role in the genetic inheritance of obesity.The expression of the IL-17A gene is significantly increased in women with morbid obesity.38We hypothesize that psoriasis and obesity may have the same genetic susceptibility loci regarding IL-17A,which constitutes a common pathophysiological basis.This issue warrants further exploration.

We speculate that the increased risk of psoriasis in obese patients may be due to the common chronic inflammatory state,as suggested by Kanemaru et al.39They found that obesity aggravates psoriasis dermatitis in mice by upregulating the expression of IL-17A,IL-22,and regenerating islet-derived 3γ.Obesity is not only related to the incidence and severity of psoriasis,but also affects the therapeutic response.Obesity changes the pharmacokinetics of drugs and increases the drug clearance,thus resulting in a shortened half-life and reduced serum concentration.In addition,obesity makes the body enter a immunodepressive state,losing the normal immune response.40A retrospective multicenter study conducted in Italy reported that the mean PASI of the group with obesity with psoriasis was significantly higher than that of the non-obese group,and seemed to be related to the disease severity and the lower response to secukinumab.41Singh et al.42also discovered that the treatment failure rate of anti-TNF therapy in patients who were overweight/obese was 60%higher than that in normal cases,and even patients with obesity treated via weight-based regimens(such as infliximab)had an inferior response to therapy.Other studies have revealed that weight reduction may be helpful in the treatment of psoriasis.Naldi et al.43showed that the disease severity of psoriatic patients who were overweight or obese was significantly reduced after 20 weeks of diet intervention and enhanced exercise.Data from numerous studies have shown that a high-fat,highcalorie diet might be the main mechanism of obesity.44Furthermore,recent studies have shown that a high-fat diet exacerbates murine psoriatic dermatitis by increasing the number of IL-17-producing Th17 andγδT cells.45A highfat diet containing SFA rather than obesity itself plays an important role in the prevalence of psoriasis in patients with obesity.Therefore,adjusting the energy structure of the diet to enable patients to lose weight may be beneficial in improving the clinical manifestations of psoriasis.One study in which patients with obesity and psoriasis received biologic therapy and were randomly assigned in a 1:1 ratio to receive a low-calorie or normal diet(control group)showed that the mean weight loss at 24weeks was 12.9±1.2kg in the low-calorie diet group and 1.5±0.5kg in the control group.46The average improvement in the mean PASI score was 84% in the low-calorie diet group and 69% in the control group.46PASI 75 was achieved by 85.9%of patients in the low-calorie diet group and 59.3%of patients in the control group(P＜0.001),indicating that weight loss through diet control may increase the curative effect of biological agents.46A 24-week,randomized,controlled trial of 61 patients with obesity with moderateto-severe psoriasis found that patients treated with cyclosporine combined with a calorie-controlled diet reached a higher rate of PASI 75 remission than patients treated with cyclosporine alone;thus,controlling the caloric intake may increase the response to cyclosporin.47Furthermore,long-term weight loss has a long-term,positive impact on psoriasis.However,weight loss alone may not be sufficient to maintain the remission of moderate-to-severe-psoriasis in patients with obesity.It remains controversial whether the administration of biological agents can reduce weight while improving the symptoms of psoriasis.Some studies have shown that the patients receiving secukinumab treatment for 52weeks tended to lose weight.48In contrast,others have shown that patients’weight and BMI increased after 24weeks of treatment with secukinumab,49and that the application of biological agents did not result in weight loss.50Although it remains unclear whether weight loss increases the therapeutic efficacy,it is clear that obesity has a negative effect on the occurrence,development,and treatment of psoriasis.To sum up,the increased expression of IL-17A in psoriasis and obesity may be due to the common inflammatory state,and the genetic correlation about IL-17A indirectly mediated this process.The key role of IL-17A in the pathological mechanism of psoriasis and obesity suggests the great potential of targeted biological agents for interleukin-17A combined with weight loss in the treatment of overweight or obese patients with psoriasis.

Conclusions

There is a bidirectional relationship between obesity and psoriasis because both conditions involve chronic inflammation.The duplicate role of IL-17A in the pathogenesis of obesity and psoriasis suggests that IL-17A may be crucial in mediating a continuous cycle of inflammation(Fig.1).Since there are few researches on the immune mechanism between psoriasis and obesity mediated by IL-17A,this review has following limitations:it is not very clearly described in the article about how IL-17A connect psoriasis and obesity through some specific immune pathways.Also,some potential IL-17A-related signaling pathways and inflammatory mechanisms may be omitted,which need to be further studied and explored in the future.At present,the application of anti-IL-17 therapy and other biological agents has achieved good efficacy regarding the clinical relief of psoriasis symptoms,but the treatment of patients with concomitant obesity and psoriasis remains challenging.A better clinical effect with fewer complications is achieved when dietary and lifestyle modifications to reduce weight are implemented in combination with medical treatment.

Figure 1.Common pathophysiological basis of obesity and psoriasis regarding IL-17.IL-17:interleukin-17.

Source of funding

This work was supported by a grant from the National Natural Science Foundation of China(No.81773326).