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Psoriasis: Past, Present, and Future

      Abbreviations:

      HLA (human leukocyte antigen), Psa (psoriatic arthritis), TCR (T cell receptor)
      Psoriasis is a chronic inflammatory disease of the skin, nails, and joints. In the last two decades, there has been enormous progress in our understanding of the genetics, immunology, and associated comorbidities (Figure 1). This has been accompanied by a marked improvement in the number of therapeutic agents and their effectiveness. Much of this progress has been outlined in numerous articles, commentaries and reviews in the Journal of Investigative Dermatology (JID) over the years (Figure 2). This commentary, which is part of the JID Collections, serves to outline how we have arrived at our present state of knowledge on psoriasis and provides an overview of some exciting future directions.
      Figure thumbnail gr1
      Figure 1Simplified overview of interrelation between psoriasis predisposing factors, inflammatory mechanisms, clinical manifestations, and consequences. Crosstalk between the innate and adaptive immune systems involves secretion of IL-12 and IL-23, which are important for priming and maintaining Th1 and Th17 responses. Inflammatory responses prime keratinocytes that in turn amplify the inflammatory response and “feed forward,” creating a sustaining cycle of inflammation. These inflammatory responses shape the clinical manifestations of psoriasis, which exist between pustular forms (dominated by higher IL-36 responses) and plaque psoriasis (characterized by high IL-17A).
      Figure thumbnail gr2
      Figure 2Number of psoriasis publications in the Journal of Investigative Dermatology (JID) per year since 1945.

      Historical perspective

      For many decades, psoriasis was thought to be a disease characterized by keratinocyte hyperplasia (Figure 3). This was the main motivation for use of the anti-proliferative chemotherapy agent methotrexate for treatment of psoriasis (
      • Weinstein G.D.
      • Frost P.
      Abnormal cell proliferation in psoriasis.
      ,
      • Weinstein G.D.
      • Velasco J.
      Selective action of methotrexate on psoriatic epidermal cells.
      ) (Figure 4). Its therapeutic benefit was attributed primarily to direct effects of methotrexate on the skin (
      • Weinstein G.D.
      • McCullough J.L.
      Cytokinetics and chemotherapy of psoriasis.
      ).
      Figure thumbnail gr3
      Figure 3Timeline of discoveries in genetics and (top) genomics of psoriasis and (bottom) pathogenesis of psoriasis.
      Figure thumbnail gr4
      Figure 4Timeline of discoveries of psoriasis (top) comorbidities and (bottom) treatment. MI, myocardial infarction.
      Related to the focus on hyperproliferation of the psoriatic epidermis was research on cyclic AMP (
      • Voorhees J.J.
      • Duell E.A.
      • Bass L.J.
      • Powell J.A.
      • Harrell E.R.
      The cyclic AMP system in normal and psoriatic epidermis.
      ) and inhibitors of phosphodiesterases (PDE) as potential therapeutic agents in psoriasis (
      • Rusin L.J.
      • Duell E.A.
      • Voorhees J.J.
      Papaverine and Ro 20-1724 inhibit cyclic nucleotide phosphodiesterase activity and increase cyclic AMP levels in psoriatic epidermis in vitro.
      ,
      • Stawiski M.A.
      • Powell J.A.
      • Lang P.G.
      • Schork A.
      • Duell E.A.
      • Voorhees J.J.
      Papaverine: its effects on cyclic AMP in vitro and psoriasis in vivo.
      ,
      • Stawiski M.A.
      • Rusin L.J.
      • Burns T.L.
      • Weinstein G.D.
      • Voorhees J.J.
      Ro 20-1724: an agent that significantly improves psoriatic lesions in double-blind clinical trials.
      ) – work that predated development and use of the PDE4 antagonist apremilast as a psoriasis therapy (
      • Nast A.
      • Jacobs A.
      • Rosumeck S.
      • Werner R.N.
      Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis: a systematic review and meta-analysis.
      ) by several decades.
      As the discrete nature of psoriatic plaques suggested a local phenomenon, there was a hunt for a hormone or similar messenger directing localized genesis of lesions. While cyclic AMP garnered much attention, the arachidonic acid derivative leukotriene B4 (LTB4) also emerged as a likely candidate, as it was increased in psoriatic plaques (
      • Brain S.
      • Camp R.
      • Dowd P.
      • Black A.K.
      • Greaves M.
      The release of leukotriene B4-like material in biologically active amounts from the lesional skin of patients with psoriasis.
      ,
      • Brain S.D.
      • Camp R.D.
      • Dowd P.M.
      • Black A.K.
      • Woollard P.M.
      • Mallet A.I.
      • et al.
      Psoriasis and leukotriene B4.
      ,
      • Grabbe J.
      • Czarnetzki B.M.
      • Mardin M.
      Chemotactic leukotrienes in psoriasis.
      ) and had mitogenic effects on keratinocytes (
      • Bauer F.W.
      • van de Kerkhof P.C.
      • Maassen-de Grood R.M.
      Epidermal hyperproliferation following the induction of microabscesses by leukotriene B4.
      ,
      • Kragballe K.
      • Desjarlais L.
      • Voorhees J.J.
      Leukotrienes B4, C4 and D4 stimulate DNA synthesis in cultured human epidermal keratinocytes.
      ). Cyclosporine, an inhibitor of phospholipase A2 (
      • Fan T.P.
      • Lewis G.P.
      Mechanism of cyclosporin A-induced inhibition of prostacyclin synthesis by macrophages.
      ) and therefore potential suppressor of LTB4 production, thus surfaced as a potential anti-psoriatic agent.
      In 1979, a small case series of four patients treated with cyclosporine was published in the New England Journal of Medicine (
      • Mueller W.
      • Herrmann B.
      Cyclosporin A for psoriasis.
      ), followed 5 years later by a single case report in the Lancet in 1984 (
      • Harper J.I.
      • Keat A.C.
      • Staughton R.C.
      Cyclosporin for psoriasis.
      ). In 1986, two clinical trials motivated in part by the LTB4 findings demonstrated conclusively the clinical efficacy of cyclosporine for chronic plaque psoriasis (
      • Ellis C.N.
      • Gorsulowsky D.C.
      • Hamilton T.A.
      • Billings J.K.
      • Brown M.D.
      • Headington J.T.
      • et al.
      Cyclosporine improves psoriasis in a double-blind study.
      ,
      • Griffiths C.E.
      • Powles A.V.
      • Leonard J.N.
      • Fry L.
      • Baker B.S.
      • Valdimarsson H.
      Clearance of psoriasis with low dose cyclosporin.
      ). While lesional LTB4 was found to decrease with treatment (
      • Ellis C.N.
      • Gorsulowsky D.C.
      • Hamilton T.A.
      • Billings J.K.
      • Brown M.D.
      • Headington J.T.
      • et al.
      Cyclosporine improves psoriasis in a double-blind study.
      ), the dramatic response prompted consideration of an alternative hypothesis – that the primary defect in psoriasis was not keratinocyte hyperproliferation but rather immunologic in nature. This represented a watershed moment in psoriasis research, rapidly shifting the focus toward the immune system, and particularly T cells, as a critical pathogenic driver (
      • Gottlieb A.B.
      • Grossman R.M.
      • Khandke L.
      • Carter D.M.
      • Sehgal P.B.
      • Fu S.M.
      • et al.
      Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation.
      ). Further work demonstrating disease improvement with selective blockade of activated T cells by interleukin (IL)-2 conjugated to diphtheria toxin fragments definitively implicated T cells in psoriasis pathogenesis (
      • Gottlieb S.L.
      • Gilleaudeau P.
      • Johnson R.
      • Estes L.
      • Woodworth T.G.
      • Gottlieb A.B.
      • et al.
      Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.
      ).
      In 1991 Brian Nickoloff proposed the idea of the “cytokine network” in psoriasis (
      • Nickoloff B.J.
      The cytokine network in psoriasis.
      ,
      • Uyemura K.
      • Yamamura M.
      • Fivenson D.F.
      • Modlin R.L.
      • Nickoloff B.J.
      The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response.
      ). In the “cytokine network” hypothesis, inflammatory cells and keratinocytes interact to drive the inflammatory process through secretion of various pro-inflammatory cytokines. Initial work focused primarily on the cytokines interferon (IFN)-γ and tumor necrosis factor (TNF)-α (
      • Uyemura K.
      • Yamamura M.
      • Fivenson D.F.
      • Modlin R.L.
      • Nickoloff B.J.
      The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response.
      ).
      However, in 1998, IL-17A involvement was first recognized (
      • Teunissen M.B.
      • Koomen C.W.
      • de Waal Malefyt R.
      • Wierenga E.A.
      • Bos J.D.
      Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes.
      ). Subsequently, psoriasis was shown to contain discrete populations of T helper (Th)1 and Th17 lymphocytes (
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ). Whereas IL-12 is primarily responsible for driving Th1 responses, IL-23 has a key role in maintaining Th17 responses (
      • Stritesky G.L.
      • Yeh N.
      • Kaplan M.H.
      IL-23 promotes maintenance but not commitment to the Th17 lineage.
      ). IL-12 and IL-23 are closely related heterodimers (consisting of two subunits), each including a common p40 subunit, with IL-12 having a p35 subunit and IL-23 a p19 subunit (
      • Lee E.
      • Trepicchio W.L.
      • Oestreicher J.L.
      • Pittman D.
      • Wang F.
      • Chamian F.
      • et al.
      Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.
      ). In 2004, it was noted that while the p40 and p19 subunits were prominently expressed in psoriatic skin, the p35 subunit was decreased (
      • Lee E.
      • Trepicchio W.L.
      • Oestreicher J.L.
      • Pittman D.
      • Wang F.
      • Chamian F.
      • et al.
      Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.
      ), suggesting that IL-23 with its p19 subunit plays a more dominant role than IL-12, and therefore Th1 responses, in psoriasis.
      Genetic studies align with these observations, showing association between psoriasis and variants close to the p40 gene (IL12B) and within the IL-23 receptor (IL23R) (
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ), as well as NF-κB (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ) and the IL-17 signaling pathway (
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • Nair R.P.
      • Debrus S.
      • Raelson J.V.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ).
      This has consolidated the view of the cytokine network in psoriasis anchored by IL-23/IL-17/TNF responses (
      • Martin D.A.
      • Towne J.E.
      • Kricorian G.
      • Klekotka P.
      • Gudjonsson J.E.
      • Krueger J.G.
      • et al.
      The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings.
      ), not only in chronic plaque psoriasis but also in other psoriasis subtypes (
      • Xing X.
      • Liang Y.
      • Sarkar M.K.
      • Wolterink L.
      • Swindell W.R.
      • Voorhees J.J.
      • et al.
      IL-17 responses are the dominant inflammatory signal linking inverse, erythrodermic, and chronic plaque psoriasis.
      ). The foundational role of the “cytokine network” in psoriasis has been conclusively demonstrated by the remarkable efficacy of drugs targeting various cytokines in psoriasis including TNF, IL-17A and more recently IL-23 (
      • Chaudhari U.
      • Romano P.
      • Mulcahy L.D.
      • Dooley L.T.
      • Baker D.G.
      • Gottlieb A.B.
      Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial.
      ,
      • Gordon K.B.
      • Duffin K.C.
      • Bissonnette R.
      • Prinz J.C.
      • Wasfi Y.
      • Li S.
      • et al.
      A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis.
      ,
      • Gordon K.B.
      • Strober B.
      • Lebwohl M.
      • Augustin M.
      • Blauvelt A.
      • Poulin Y.
      • et al.
      Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials.
      ,
      • Langley R.G.
      • Elewski B.E.
      • Lebwohl M.
      • Reich K.
      • Griffiths C.E.
      • Papp K.
      • et al.
      Secukinumab in plaque psoriasis--results of two phase 3 trials.
      ,
      • Leonardi C.
      • Matheson R.
      • Zachariae C.
      • Cameron G.
      • Li L.
      • Edson-Heredia E.
      • et al.
      Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.
      ,
      • Papp K.A.
      • Leonardi C.
      • Menter A.
      • Ortonne J.P.
      • Krueger J.G.
      • Kricorian G.
      • et al.
      Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis.
      ,
      • Reich K.
      • Papp K.A.
      • Blauvelt A.
      • Tyring S.K.
      • Sinclair R.
      • Thaci D.
      • et al.
      Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials.
      ,
      • Reich K.
      • Rich P.
      • Maari C.
      • Bissonnette R.
      • Leonardi C.
      • Menter A.
      • et al.
      Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study.
      ).
      Recently, a “feed forward” mechanism as a driver of psoriasis pathogenesis has been proposed by James Krueger and colleagues (
      • Hawkes J.E.
      • Chan T.C.
      • Krueger J.G.
      Psoriasis pathogenesis and the development of novel targeted immune therapies.
      ). This proposed mechanism links together the “cytokine network” with the epidermal responses and hyperplasia, as follows: activation and increased expression of IL-17 in pre-psoriatic skin produces a feed forward inflammatory response in keratinocytes that is self-amplifying and drives the development of psoriatic plaques through induction of epidermal cell proliferation, hyperplasia, and further recruitment of inflammatory cells into the skin (
      • Hawkes J.E.
      • Chan T.C.
      • Krueger J.G.
      Psoriasis pathogenesis and the development of novel targeted immune therapies.
      ). This model more readily enables incorporation of other inflammatory mediators and processes such as for the epidermal derived cytokines such as IL-17C (
      • Fritz Y.
      • Klenotic P.A.
      • Swindell W.R.
      • Yin Z.Q.
      • Groft S.G.
      • Zhang L.
      • et al.
      Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.
      ,
      • Guttman-Yassky E.
      • Krueger J.G.
      IL-17C: A unique epithelial cytokine with potential for targeting across the spectrum of atopic dermatitis and psoriasis.
      ), the IL-36 family of cytokines (
      • Carrier Y.
      • Ma H.L.
      • Ramon H.E.
      • Napierata L.
      • Small C.
      • O'Toole M.
      • et al.
      Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis.
      ,
      • Johnston A.
      • Xing X.
      • Guzman A.M.
      • Riblett M.
      • Loyd C.M.
      • Ward N.L.
      • et al.
      IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression.
      ), and signaling pathways such as TNFAIP3 (
      • Devos M.
      • Mogilenko D.A.
      • Fleury S.
      • Gilbert B.
      • Becquart C.
      • Quemener S.
      • et al.
      Keratinocyte Expression of A20/TNFAIP3 Controls Skin Inflammation Associated with Atopic Dermatitis and Psoriasis.
      ), CARD14 (
      • Mellett M.
      • Meier B.
      • Mohanan D.
      • Schairer R.
      • Cheng P.
      • Satoh T.K.
      • et al.
      CARD14 Gain-of-Function Mutation Alone Is Sufficient to Drive IL-23/IL-17-Mediated Psoriasiform Skin Inflammation In Vivo.
      ), and MCPIP1, a regulator of IL-17A and IL-17C responses in psoriatic epidermis (
      • Monin L.
      • Gudjonsson J.E.
      • Childs E.E.
      • Amatya N.
      • Xing X.
      • Verma A.H.
      • et al.
      MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation.
      ,
      • Ruiz-Romeu E.
      • Ferran M.
      • Gimenez-Arnau A.
      • Bugara B.
      • Lipert B.
      • Jura J.
      • et al.
      MCPIP1 RNase is aberrantly distributed in psoriatic epidermis and rapidly induced by IL-17A.
      ), into the pathogenesis of psoriasis.
      Thus, the pathogenesis of psoriasis continues to evolve after decades of intense study, and pathogenesis remains the most highly represented area of investigation in the JID’s body of recent psoriasis literature (Figure 5).
      Figure thumbnail gr5
      Figure 5Areas of research focus for psoriasis publications in the Journal of Investigative Dermatology (JID) in the preceding 2 years. Subcategorization reveals predominant focus on pathogenesis, drug responses, and clinical outcomes but also a strong emphasis on epidemiology and comorbidities. Literature search includes JID publications from July 2017 through June 2019 containing the search term “psoria*” with direct relevance to psoriasis. Some topics are common to multiple publications but represented only once in the figure. Many publications could be appropriately classified in multiple ways; the figure is intended to provide an overall impression of distribution of scientific focus. AD, atopic dermatitis; AGEP, acute generalized exanthematous pustulosis; BSA, body surface area; CV, cardiovascular; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; IMQ, imiquimod; KC, keratinocyte; LCE, late cornified envelope; NETs, neutrophil extracellular traps; sPGA, static physician global assessment; TLRs, toll-like receptors.

      Comorbidities of psoriasis

      Due to strong associations with a multitude of comorbidities, psoriasis is increasingly conceptualized as a systemic inflammatory disease. While psoriasis is classically associated with psoriatic arthritis, there is mounting evidence for associations with cardiometabolic disease, immune-mediated inflammatory disease, malignancy, and infection. In many cases, whether these associations are evidence of spillover of cutaneous inflammation, shared susceptibility, or pervasive immune dysregulation remains to be determined.
      Cardiometabolic disease has been reported in association with psoriasis for over a century (
      • Strauss H.
      Zur Lehre von der neurogenen und der thyreogenen Glykosurie.
      ). Since 2000, there has been a marked proliferation in publications describing these associations (
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ,
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      • Gelfand J.M.
      Prevalence of cardiovascular risk factors in patients with psoriasis.
      ,
      • Sommer D.M.
      • Jenisch S.
      • Suchan M.
      • Christophers E.
      • Weichenthal M.
      Increased prevalence of the metabolic syndrome in patients with moderate to severe psoriasis.
      ), with severe psoriasis conferring higher risk. With regard to cardiovascular disease, these studies generally promoted the hypothesis that chronic skin inflammation and the concomitant increase in circulating proinflammatory cytokines favor development of atherosclerosis and that systemic anti-psoriatic therapy may protect against this process and consequent adverse cardiovascular outcomes. Indeed, studies have demonstrated reductions in major adverse cardiovascular events (MACE) in psoriasis patients on TNF-α antagonists (
      • Ahlehoff O.
      • Skov L.
      • Gislason G.
      • Gniadecki R.
      • Iversen L.
      • Bryld L.E.
      • et al.
      Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort.
      ,
      • Wu J.J.
      • Poon K.Y.
      • Channual J.C.
      • Shen A.Y.
      Association between tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis.
      ).
      However, the mechanism may not be so straightforward: circulating inflammatory markers decrease in as little as 4 weeks in psoriasis patients treated with anti-TNF-α therapy (
      • Kim J.
      • Tomalin L.
      • Lee J.
      • Fitz L.J.
      • Berstein G.
      • Correa-da Rosa J.
      • et al.
      Reduction of Inflammatory and Cardiovascular Proteins in the Blood of Patients with Psoriasis: Differential Responses between Tofacitinib and Etanercept after 4 Weeks of Treatment.
      ), yet 52 weeks of anti-TNF-α therapy had no effect on vascular inflammation in the ascending aorta and in fact slightly increased vascular inflammation in the carotids (
      • Bissonnette R.
      • Harel F.
      • Krueger J.G.
      • Guertin M.C.
      • Chabot-Blanchet M.
      • Gonzalez J.
      • et al.
      TNF-alpha Antagonist and Vascular Inflammation in Patients with Psoriasis Vulgaris: A Randomized Placebo-Controlled Study.
      ).
      More recently, the question of whether obesity promotes psoriasis was tackled using a powerful approach called Mendelian randomization (
      • Budu-Aggrey A.
      • Paternoster L.
      Research Techniques Made Simple: Using Genetic Variants for Randomization.
      ) that overcomes challenges of observational epidemiological studies in which reverse causation or confounding factors may obscure causality. The technique uses genetic variants as proxies – termed instruments – for relevant exposures. Allotted randomly at conception, genetic variants are independent from confounders and the outcome itself and thus can be used to estimate the effect of the exposure on the outcome. As psoriasis has long represented a thriving forefront for genome-wide association studies (
      • Elder J.T.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Stuart P.E.
      • Tejasvi T.
      • et al.
      Molecular dissection of psoriasis: integrating genetics and biology.
      ), a nearly unparalleled amount of genetic data for psoriasis patients has been amassed. Psoriasis is thus particularly well positioned for approaches such as Mendelian randomization. Analyses of these large datasets using obesity-associated genetic variants as a proxy for actual measured body mass index (BMI) strongly suggested that higher BMI causally increases risk of psoriasis; the converse analyses showed little to no causal effect of psoriasis genetic risk on BMI (
      • Budu-Aggrey A.
      • Brumpton B.
      • Tyrrell J.
      • Watkins S.
      • Modalsli E.H.
      • Celis-Morales C.
      • et al.
      Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study.
      ,
      • Ogawa K.
      • Stuart P.E.
      • Tsoi L.C.
      • Suzuki K.
      • Nair R.P.
      • Mochizuki H.
      • et al.
      A Transethnic Mendelian Randomization Study Identifies Causality of Obesity on Risk of Psoriasis.
      ). Additional comorbid conditions will likely benefit from similar analysis to help deconvolute the complex relationships between psoriasis and cardiometabolic diseases.
      For some psoriasis comorbidities, however, there is direct evidence that the association is due not to unidirectional causality but rather to shared susceptibility. This is best exemplified by the overlap of genetic risk variants – many of which affect immune regulatory genes – between psoriasis and certain associated conditions. Chief among these is Crohn’s disease, but shared risk loci have also been identified for diseases such as type II diabetes mellitus that are not classically considered to be autoinflammatory (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ,
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ,
      • Wolf N.
      • Quaranta M.
      • Prescott N.J.
      • Allen M.
      • Smith R.
      • Burden A.D.
      • et al.
      Psoriasis is associated with pleiotropic susceptibility loci identified in type II diabetes and Crohn disease.
      ). As might be anticipated for conditions with shared susceptibility, incident Crohn’s disease is more common among psoriasis patients (
      • Li W.Q.
      • Han J.L.
      • Chan A.T.
      • Qureshi A.A.
      Psoriasis, psoriatic arthritis and increased risk of incident Crohn's disease in US women.
      ), and incident psoriasis is more common among patients with Crohn’s disease (
      • Egeberg A.
      • Thyssen J.P.
      • Burisch J.
      • Colombel J.F.
      Incidence and Risk of Inflammatory Bowel Disease in Patients with Psoriasis-A Nationwide 20-Year Cohort Study.
      ). Also not unexpectedly, these conditions share many therapies, and investigations into their immunopathogenesis have revealed considerable similarities.
      For psoriatic arthritis (PsA), the best-known psoriasis comorbidity, both shared genetic susceptibility and spillover of cutaneous inflammation likely contribute to the association. PsA and psoriasis susceptibility genes are largely overlapping, yet variants have been identified that are more strongly associated with PsA than psoriasis (
      • Ellinghaus E.
      • Stuart P.E.
      • Ellinghaus D.
      • Nair R.P.
      • Debrus S.
      • Raelson J.V.
      • et al.
      Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL.
      ,
      • Stuart P.E.
      • Nair R.P.
      • Tsoi L.C.
      • Tejasvi T.
      • Das S.
      • Kang H.M.
      • et al.
      Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture.
      ), suggesting the possibility of independent genetic drivers for PsA. However, PsA is generally diagnosed after the appearance of cutaneous psoriasis and seldom occurs in the absence of cutaneous psoriasis, and data indicate that cutaneous inflammation of psoriasis may exacerbate or even directly drive PsA: development of joint disease in a genetic mouse model of autoimmune arthritis is dramatically accelerated in the presence of psoriasis-like skin inflammation due to hyperactivation of Stat3 in the epidermis (
      • Yamamoto M.
      • Nakajima K.
      • Takaishi M.
      • Kitaba S.
      • Magata Y.
      • Kataoka S.
      • et al.
      Psoriatic inflammation facilitates the onset of arthritis in a mouse model.
      ). Furthermore, epidermally restricted hyperactivation (
      • Winge M.C.
      • Ohyama B.
      • Dey C.N.
      • Boxer L.M.
      • Li W.
      • Ehsani-Chimeh N.
      • et al.
      RAC1 activation drives pathologic interactions between the epidermis and immune cells.
      ) or deletion (
      • Zenz R.
      • Eferl R.
      • Kenner L.
      • Florin L.
      • Hummerich L.
      • Mehic D.
      • et al.
      Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins.
      ) of genes implicated in human psoriasis can promote spontaneous development of PsA-like joint disease. Thus, controlling cutaneous psoriasis may be of benefit in preventing or limiting joint disease, lending credence to the concept of PsA as a ‘disease within a disease’ (
      • Eder L.
      • Chandran V.
      • Pellett F.
      • Pollock R.
      • Shanmugaragjah S.
      • Rosen C.F.
      • et al.
      IL13 gene polymorphism is a marker for psoriatic arthritis among psoriasis patients.
      ).
      While not entirely distinct from the above mechanisms, a third possible explanation for psoriasis comorbidities is pervasive immune dysregulation. This mechanism is often invoked for associations of psoriasis with malignancy and infection. In one nationwide study, malignancy carried the highest absolute and excess risks of death in psoriasis (
      • Lee M.S.
      • Yeh Y.C.
      • Chang Y.T.
      • Lai M.S.
      All-cause and cause-specific mortality in patients with psoriasis in Taiwan: a nationwide population-based study.
      ). In larger cohort and meta-analysis studies, patients with psoriasis show higher risks for multiple cancers, particularly lymphohematopoietic malignancy, that persist even when controlling for confounders such as increased smoking and alcohol consumption among psoriasis patients and use of potentially malignancy-promoting anti-psoriatic therapies (
      • Brauchli Y.B.
      • Jick S.S.
      • Miret M.
      • Meier C.R.
      Psoriasis and risk of incident cancer: an inception cohort study with a nested case-control analysis.
      ,
      • Lee M.S.
      • Yeh Y.C.
      • Chang Y.T.
      • Lai M.S.
      All-cause and cause-specific mortality in patients with psoriasis in Taiwan: a nationwide population-based study.
      ,
      • Pouplard C.
      • Brenaut E.
      • Horreau C.
      • Barnetche T.
      • Misery L.
      • Richard M.A.
      • et al.
      Risk of cancer in psoriasis: a systematic review and meta-analysis of epidemiological studies.
      ).
      In the case of lymphoma, many have posited that the chronically dysregulated immune state of psoriasis drives increased risk. Now in the era of immunotherapy, as our understanding of the critical role of the immune system in limiting malignancy increases, it is tempting to speculate that immune dysregulation and associated impairment of antineoplastic immune surveillance underlies all excess malignancy risk among psoriasis patients. However, this will be challenging to ever prove. Chronic immune dysfunction also likely contributes to the increased risk of serious infections that is observed in patients with psoriasis, even when excluding those on immunosuppressive therapies (
      • Takeshita J.
      • Shin D.B.
      • Ogdie A.
      • Gelfand J.M.
      Risk of serious infection, opportunistic infection, and herpes zoster among patients with psoriasis in the United Kingdom.
      ).
      While the true natures of the relationships between psoriasis and associated conditions have proven difficult to define, investigations of their intersection continue to advance understanding of psoriasis immunopathogenesis and guide therapeutic pursuits. Accordingly, publications addressing epidemiology and comorbidities are now well represented research in the JID psoriasis literature (Figure 5).

      Modeling of psoriasis – mouse models and beyond

      With two reported exceptions, a rhesus monkey and a cynomolgus monkey, psoriasis is not observed in animals other than humans (
      • Gudjonsson J.E.
      • Johnston A.
      • Dyson M.
      • Valdimarsson H.
      • Elder J.T.
      Mouse models of psoriasis.
      ). However, over the past three decades, numerous mouse models of psoriasis have been described, created through genetic modifications, topical application, or intradermal cytokine injection. Furthermore, various non-animal in vitro models such as the epidermal raft system (
      • Barker C.L.
      • McHale M.T.
      • Gillies A.K.
      • Waller J.
      • Pearce D.M.
      • Osborne J.
      • et al.
      The development and characterization of an in vitro model of psoriasis.
      ,
      • Gordon K.
      • Kochkodan J.J.
      • Blatt H.
      • Lin S.Y.
      • Kaplan N.
      • Johnston A.
      • et al.
      Alteration of the EphA2/Ephrin-A signaling axis in psoriatic epidermis.
      ) have been developed; these have become more frequently used in recent years, and many of these landmark advances in psoriasis have been published in the JID.
      The first mouse model of psoriasis described was a xenograft model in which lesional psoriatic skin was grafted onto congenitally athymic (nude) mice (
      • Krueger G.G.
      • Manning D.D.
      • Malouf J.
      • Ogden B.
      Long-term maintenance of psoriatic human skin on congenitally athymic (nude) mice.
      ). These mice lack a thymus and are therefore unable to mount an immune response against the grafted skin, enabling maintenance of the skin graft for up to 11 weeks.
      A major step forward was made in 2004 when spontaneous development of psoriasis was described in a novel xenograft model where non-lesional psoriatic skin spontaneously developed histologic hallmarks of psoriasis after grafting (
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • Nickoloff B.J.
      • Suter M.
      • Nestle F.O.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      ). This model is uniquely dependent upon the recipient mouse, which is deficient in type I and type II interferon receptors along with being deficient in the recombination activating gene 2 (Rag2), as this spontaneous development of psoriasis-like disease is not observed with skin grafting onto other immunodeficient mouse strains. This model has been used to show the importance of plasmacytoid dendritic cells in initiation of psoriasis (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.
      ), role of epidermal T cells (
      • Conrad C.
      • Boyman O.
      • Tonel G.
      • Tun-Kyi A.
      • Laggner U.
      • de Fougerolles A.
      • et al.
      Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis.
      ), and role of CD8+ T cells (
      • Di Meglio P.
      • Villanova F.
      • Navarini A.A.
      • Mylonas A.
      • Tosi I.
      • Nestle F.O.
      • et al.
      Targeting CD8(+) T cells prevents psoriasis development.
      ).
      The majority of the spontaneous and transgenic mouse models of psoriasis were developed and described in the mid-1990s to mid-to-late 2000s (
      • Gudjonsson J.E.
      • Johnston A.
      • Dyson M.
      • Valdimarsson H.
      • Elder J.T.
      Mouse models of psoriasis.
      ,
      • Hawkes J.E.
      • Adalsteinsson J.A.
      • Gudjonsson J.E.
      • Ward N.L.
      Research Techniques Made Simple: Murine Models of Human Psoriasis.
      ). Over 40 unique mouse models have been described (
      • Hawkes J.E.
      • Adalsteinsson J.A.
      • Gudjonsson J.E.
      • Ward N.L.
      Research Techniques Made Simple: Murine Models of Human Psoriasis.
      ). With the initial description of the imiquimod (IMQ) inducible model of psoriasis (
      • van der Fits L.
      • Mourits S.
      • Voerman J.S.
      • Kant M.
      • Boon L.
      • Laman J.D.
      • et al.
      Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.
      ) and cytokine injection models (
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ), acute or inducible models have rapidly become one of the most widely used systems for studying human psoriasis (
      • Hawkes J.E.
      • Adalsteinsson J.A.
      • Gudjonsson J.E.
      • Ward N.L.
      Research Techniques Made Simple: Murine Models of Human Psoriasis.
      ). Recent examples of the utilization of this model include the demonstration of IL-1β/IL-1R signaling pathway in skin inflammation (
      • Cai Y.
      • Xue F.
      • Quan C.
      • Qu M.
      • Liu N.
      • Zhang Y.
      • et al.
      A Critical Role of the IL-1beta-IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis.
      ); therapeutic intervention to determine the response to topical tacrolimus (
      • Pischon H.
      • Radbruch M.
      • Ostrowski A.
      • Schumacher F.
      • Honzke S.
      • Kleuser B.
      • et al.
      How Effective Is Tacrolimus in the Imiquimod-Induced Mouse Model of Psoriasis?.
      ); link between skin inflammation and hyperglycemia (
      • Ikumi K.
      • Odanaka M.
      • Shime H.
      • Imai M.
      • Osaga S.
      • Taguchi O.
      • et al.
      Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice.
      ); role of IL-20 receptor signaling (
      • Ha H.L.
      • Wang H.
      • Claudio E.
      • Tang W.
      • Siebenlist U.
      IL-20-receptor signaling delimits IL-17 production in psoriatic inflammation.
      ) and IL-17E (
      • Senra L.
      • Mylonas A.
      • Kavanagh R.D.
      • Fallon P.G.
      • Conrad C.
      • Borowczyk-Michalowska J.
      • et al.
      IL-17E (IL-25) Enhances Innate Immune Responses during Skin Inflammation.
      ) in psoriasis pathogenesis; and to elucidate the function of Trim32 in psoriasis and atopic dermatitis (
      • Liu Y.
      • Wang Z.
      • De La Torre R.
      • Barling A.
      • Tsujikawa T.
      • Hornick N.
      • et al.
      Trim32 deficiency enhances Th2 immunity and predisposes to features of atopic dermatitis.
      ). However, some concerns have been raised about the overutilization of this model and its variability depending on the mouse strain used (
      • Swindell W.R.
      • Michaels K.A.
      • Sutter A.J.
      • Diaconu D.
      • Fritz Y.
      • Xing X.
      • et al.
      Imiquimod has strain-dependent effects in mice and does not uniquely model human psoriasis.
      ). Nonetheless, since the first report of this model in 2009, the IMQ psoriasis-like model has been used in over 200 publications (
      • Hawkes J.E.
      • Chan T.C.
      • Krueger J.G.
      Psoriasis pathogenesis and the development of novel targeted immune therapies.
      ).
      Other models entail intradermal injection of pro-inflammatory cytokines, with the first instance of this reported in 2003 with IL-23 (
      • Kopp T.
      • Lenz P.
      • Bello-Fernandez C.
      • Kastelein R.A.
      • Kupper T.S.
      • Stingl G.
      IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity.
      ), and later with injections of IL-22 (
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ), IL-21 (
      • Caruso R.
      • Botti E.
      • Sarra M.
      • Esposito M.
      • Stolfi C.
      • Diluvio L.
      • et al.
      Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis.
      ), and most recently IL-36A (
      • Campbell J.J.
      • Ebsworth K.
      • Ertl L.S.
      • McMahon J.P.
      • Wang Y.
      • Yau S.
      • et al.
      Efficacy of Chemokine Receptor Inhibition in Treating IL-36alpha-Induced Psoriasiform Inflammation.
      ). Other publications in the JID exploiting these models have explored the role of IL-6 (
      • Lindroos J.
      • Svensson L.
      • Norsgaard H.
      • Lovato P.
      • Moller K.
      • Hagedorn P.H.
      • et al.
      IL-23-mediated epidermal hyperplasia is dependent on IL-6.
      ), superoxide dismutase (
      • Lee Y.S.
      • Cheon I.S.
      • Kim B.H.
      • Kwon M.J.
      • Lee H.W.
      • Kim T.Y.
      Loss of extracellular superoxide dismutase induces severe IL-23-mediated skin inflammation in mice.
      ), and the toll-like-receptors (TLRs) 7, 8, and 9 in psoriasis (
      • Jiang W.
      • Zhu F.G.
      • Bhagat L.
      • Yu D.
      • Tang J.X.
      • Kandimalla E.R.
      • et al.
      A Toll-like receptor 7, 8, and 9 antagonist inhibits Th1 and Th17 responses and inflammasome activation in a model of IL-23-induced psoriasis.
      ). The raft models have also been used to explore specific mechanisms in psoriasis including glucocorticoid deficiency in lesional psoriatic skin (
      • Sarkar M.K.
      • Kaplan N.
      • Tsoi L.C.
      • Xing X.
      • Liang Y.
      • Swindell W.R.
      • et al.
      Endogenous glucocorticoid deficiency in psoriasis promotes inflammation and abnormal differentiation.
      ) and biology of Ephrin-A signaling (
      • Gordon K.
      • Kochkodan J.J.
      • Blatt H.
      • Lin S.Y.
      • Kaplan N.
      • Johnston A.
      • et al.
      Alteration of the EphA2/Ephrin-A signaling axis in psoriatic epidermis.
      ).
      Complex diseases such as psoriasis create a formidable challenge for attempts to model pathogenesis. However, while no model can capture the entirety of psoriasis pathogenesis, these models are indispensable and help us understand the roles of specific mediators and signaling pathways.

      Future directions in psoriasis

      Despite dramatic advances in understanding of psoriasis immunopathogenesis and treatment over the last several decades, psoriasis remains a vibrant field of investigation. This is perhaps because psoriasis serves as a readily accessible – although deeply complex – immune-mediated inflammatory disease paradigm for exploration of forefronts such as the role of tissue-resident memory T cells and the interplay between metabolism and autoinflammation. These and several other emerging entities are reviewed in brief below.

      Tissue-resident memory T cells (TRMs) and the psoriasis autoantigen

      Psoriasis patients are frequently frustrated by the propensity for their psoriasis to recur at sites of previous lesions upon cessation of therapy. Early investigation of this phenomenon revealed a ‘residual disease genomic profile’ including expression of cytokines and T cell-specific transcripts in skin previously affected by psoriasis, suggesting the presence of persistent and likely disease-perpetuating memory T cells residing in resolved lesions between flares (
      • Suarez-Farinas M.
      • Fuentes-Duculan J.
      • Lowes M.A.
      • Krueger J.G.
      Resolved psoriasis lesions retain expression of a subset of disease-related genes.
      ). Shortly thereafter, these TRMs were found to include IL-22-producing CD4+ T cells and IL-17-producing CD8+ T cells (
      • Cheuk S.
      • Wiken M.
      • Blomqvist L.
      • Nylen S.
      • Talme T.
      • Stahle M.
      • et al.
      Epidermal Th22 and Tc17 cells form a localized disease memory in clinically healed psoriasis.
      ), providing a cytokine source for the instigation of recurrent lesions.
      In 2017, however, high-throughput T cell receptor (TCR) screening revealed that resolved psoriasis lesions contain oligoclonal IL-17A-producing T cell populations; some of the expressed TCR sequences were found to be identical across multiple patients but absent in skin from healthy controls and patients with other cutaneous inflammatory diseases (
      • Matos T.R.
      • O'Malley J.T.
      • Lowry E.L.
      • Hamm D.
      • Kirsch I.R.
      • Robins H.S.
      • et al.
      Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing alphabeta T cell clones.
      ). Interestingly, while γδ T cells represent the primary source of IL-17 in the IMQ psoriasis-like mouse model (
      • Laggner U.
      • Di Meglio P.
      • Perera G.K.
      • Hundhausen C.
      • Lacy K.E.
      • Ali N.
      • et al.
      Identification of a novel proinflammatory human skin-homing Vgamma9Vdelta2 T cell subset with a potential role in psoriasis.
      ,
      • Pantelyushin S.
      • Haak S.
      • Ingold B.
      • Kulig P.
      • Heppner F.L.
      • Navarini A.A.
      • et al.
      Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice.
      ), all of the most frequent putatively pathogenic T cell clones were αβ T cells. This is concordant with the findings of another high-throughput examination of T cell repertoires in psoriasis that reported that γδ T cells constitute a very small population of cutaneous psoriatic T cells and do not correlate with IL-17A expression in humans (
      • Merleev A.A.
      • Marusina A.I.
      • Ma C.
      • Elder J.T.
      • Tsoi L.C.
      • Raychaudhuri S.P.
      • et al.
      Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A.
      ).
      The presence of oligoclonal TRM populations in psoriasis has also breathed new life into a longstanding question: What is the psoriasis autoantigen? The most strongly associated psoriasis susceptibility loci correspond to specific human leukocyte antigen (HLA) alleles, particularly HLA-Cw6 (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.C.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ), consistent with the existence of autoantigen presentation to pathogenic CD8+ T cells. Multiple studies have identified candidate epidermal autoantigens, including keratinocyte proteins with similarity to streptococcal antigens (
      • Besgen P.
      • Trommler P.
      • Vollmer S.
      • Prinz J.C.
      Ezrin, maspin, peroxiredoxin 2, and heat shock protein 27: potential targets of a streptococcal-induced autoimmune response in psoriasis.
      ,
      • Valdimarsson H.
      • Thorleifsdottir R.H.
      • Sigurdardottir S.L.
      • Gudjonsson J.E.
      • Johnston A.
      Psoriasis--as an autoimmune disease caused by molecular mimicry.
      ), the antimicrobial peptide LL37 (
      • Lande R.
      • Botti E.
      • Jandus C.
      • Dojcinovic D.
      • Fanelli G.
      • Conrad C.
      • et al.
      The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.
      ), neolipid antigens (
      • Cheung K.L.
      • Jarrett R.
      • Subramaniam S.
      • Salimi M.
      • Gutowska-Owsiak D.
      • Chen Y.L.
      • et al.
      Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.
      ,
      • Kim J.H.
      • Hu Y.
      • Yongqing T.
      • Kim J.
      • Hughes V.A.
      • Le Nours J.
      • et al.
      CD1a on Langerhans cells controls inflammatory skin disease.
      ), and an HLA-C*06:02–presented melanocytic protein, ADAMTSL5, recognized by IL-17A-producing CD8+ T cells of the Vα3S1/Vβ13S1 TCR (
      • Arakawa A.
      • Siewert K.
      • Stohr J.
      • Besgen P.
      • Kim S.M.
      • Ruhl G.
      • et al.
      Melanocyte antigen triggers autoimmunity in human psoriasis.
      ,
      • Prinz J.C.
      Melanocytes: Target Cells of an HLA-C*06:02-Restricted Autoimmune Response in Psoriasis.
      ). The autoantigen presentation by HLA-Cw*06:02 in psoriasis has been characterized, and compared to other HLA-C alleles, HLA-Cw*06:02 has the greatest accessible contact area for the bound antigen, which might promote binding to greater number of T-cell receptors (
      • Wei P.
      • Yang Y.
      • Liu Z.
      • Luo Z.
      • Tu W.
      • Han J.
      • et al.
      Characterization of autoantigen presentation by HLA-C*06:02 in psoriasis.
      ). Notably, LL-37 and M-protein antigens of streptococci were all predicted to be able to be presented by HLA*06:02 (
      • Wei P.
      • Yang Y.
      • Liu Z.
      • Luo Z.
      • Tu W.
      • Han J.
      • et al.
      Characterization of autoantigen presentation by HLA-C*06:02 in psoriasis.
      ). Intriguingly, Vβ13 is among the putative pathogenic T cell clones identified by the high-throughput TCR screening approach above (
      • Matos T.R.
      • O'Malley J.T.
      • Lowry E.L.
      • Hamm D.
      • Kirsch I.R.
      • Robins H.S.
      • et al.
      Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing alphabeta T cell clones.
      ), suggesting that deeper investigation into the antigen recognition of TRMs in psoriasis may serve to definitively establish psoriasis as a primary autoimmune condition.

      Influence of metabolism on psoriasis and inflammation

      A shift in focus toward metabolism and inflammation has recently occurred. As mentioned above, obesity and the metabolic syndrome are closely linked with psoriasis, and obesity was recently shown to have a causal link to psoriasis (
      • Budu-Aggrey A.
      • Brumpton B.
      • Tyrrell J.
      • Watkins S.
      • Modalsli E.H.
      • Celis-Morales C.
      • et al.
      Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study.
      ,
      • Ogawa K.
      • Stuart P.E.
      • Tsoi L.C.
      • Suzuki K.
      • Nair R.P.
      • Mochizuki H.
      • et al.
      A Transethnic Mendelian Randomization Study Identifies Causality of Obesity on Risk of Psoriasis.
      ). High-fat diet has been shown to exacerbate psoriatic skin inflammation in a mouse model of psoriasis (
      • Herbert D.
      • Franz S.
      • Popkova Y.
      • Anderegg U.
      • Schiller J.
      • Schwede K.
      • et al.
      High-fat diet exacerbates early psoriatic skin inflammation independent of obesity: saturated fatty acids as key players.
      ,
      • Shimoura N.
      • Nagai H.
      • Fujiwara S.
      • Jimbo H.
      • Nishigori C.
      Exacerbation and prolongation of psoriasiform inflammation in diabetic obese mice: a synergistic role of CXCL5 and endoplasmic reticulum stress.
      ). Some of this effect may be mediated by fatty acids, which have been shown to shift immune responses in dendritic cells towards IL-23 and exacerbate psoriasis-like skin inflammation (
      • Mogilenko D.A.
      • Haas J.T.
      • L'Homme L.
      • Fleury S.
      • Quemener S.
      • Levavasseur M.
      • et al.
      Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR.
      ).

      Psoriasis subtypes and related insights

      While chronic plaque psoriasis, or psoriasis vulgaris, is the most common subtype of psoriasis, representing approximately 90% of all cases, research on other clinical subtypes of cutaneous psoriasis, such as inverse, erythrodermic, guttate, and pustular forms, have greatly increased in recent years. The common thread among all subtypes of psoriasis is the prominence of IL-17 responses (
      • Xing X.
      • Liang Y.
      • Sarkar M.K.
      • Wolterink L.
      • Swindell W.R.
      • Voorhees J.J.
      • et al.
      IL-17 responses are the dominant inflammatory signal linking inverse, erythrodermic, and chronic plaque psoriasis.
      ), although these appear to be present on a gradient and are less dominant in pustular forms of psoriasis, in which IL-36 activity has greater prominence (
      • Johnston A.
      • Xing X.
      • Wolterink L.
      • Barnes D.H.
      • Yin Z.
      • Reingold L.
      • et al.
      IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis.
      ). In contrast, IL-36 activity is less prominent in chronic plaque psoriasis (
      • Johnston A.
      • Xing X.
      • Guzman A.M.
      • Riblett M.
      • Loyd C.M.
      • Ward N.L.
      • et al.
      IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression.
      ). Mutation in IL36RN, encoding the IL-36 receptor antagonist, has been associated with a spectrum of psoriasis-associated pustular phenotypes (
      • Setta-Kaffetzi N.
      • Navarini A.A.
      • Patel V.M.
      • Pullabhatla V.
      • Pink A.E.
      • Choon S.E.
      • et al.
      Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes.
      ), and in particular generalized pustular psoriasis without psoriasis vulgaris (
      • Sugiura K.
      • Takemoto A.
      • Yamaguchi M.
      • Takahashi H.
      • Shoda Y.
      • Mitsuma T.
      • et al.
      The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist.
      ), reiterating the role of the IL-36 inflammatory axis in pustular subtypes of psoriasis. Interestingly, IL-36 may contribute to and promote IL-17/Th17 responses (
      • Arakawa A.
      • Vollmer S.
      • Besgen P.
      • Galinski A.
      • Summer B.
      • Kawakami Y.
      • et al.
      Unopposed IL-36 Activity Promotes Clonal CD4(+) T-Cell Responses with IL-17A Production in Generalized Pustular Psoriasis.
      ), providing a link between these two inflammatory responses beyond the role of IL-17A as one of the major inducers of IL-36 expression (
      • Carrier Y.
      • Ma H.L.
      • Ramon H.E.
      • Napierata L.
      • Small C.
      • O'Toole M.
      • et al.
      Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis.
      ).
      Furthermore, other presentations of psoriasis may be related to imbalances in the cytokine network. One example of this is the balance between TNF and type I interferon responses. A recent publication has shown that TNF blockade induces a dysregulated type I interferon response without autoimmunity in “paradoxical” psoriasis (
      • Conrad C.
      • Di Domizio J.
      • Mylonas A.
      • Belkhodja C.
      • Demaria O.
      • Navarini A.A.
      • et al.
      TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.
      ). Furthermore, IL-6 blockade can induce new-onset psoriasis-like disease (
      • Blauvelt A.
      IL-6 Differs from TNF-alpha: unpredicted clinical effects caused by IL-6 blockade in psoriasis.
      ), a phenomenon that has been explored in mouse models of psoriasis (
      • Fritz Y.
      • Klenotic P.A.
      • Swindell W.R.
      • Yin Z.Q.
      • Groft S.G.
      • Zhang L.
      • et al.
      Induction of Alternative Proinflammatory Cytokines Accounts for Sustained Psoriasiform Skin Inflammation in IL-17C+IL-6KO Mice.
      ) and clinically can present like chronic plaque psoriasis with guttate-like lesions (
      • Laurent S.
      • Le Parc J.M.
      • Clerici T.
      • Breban M.
      • Mahe E.
      Onset of psoriasis following treatment with tocilizumab.
      ). Taken together, these data suggest that variation in the cytokine network may be a key factor in shaping different clinical manifestations of psoriasis.

      Conclusion

      The historical perspective of the field of psoriasis provides many intriguing connections between past and present. Recurring characters such as the PDE inhibitors highlight how a long-lived and thriving field can shed new light on old players. Nevertheless, our understanding of psoriasis pathogenesis continues to grow deeper and our therapeutics ever more effective, and the rise of psoriasis as an archetypal systemic immune-mediated disease assures a vibrant future for psoriasis research.

      Conflict of Interest

      JEG serves on the Advisory Boards for Novartis, AbbVie, Almirall, and MiRagen. Research support was received from AbbVie , Novartis , AnaptysBio, and Celgene . ACB and JJV state no conflict of interest.

      Acknowledgments

      ACB was supported by the Dermatology Foundation and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) T32 postdoctoral research training grant ( 2T32AR007197-41 ).

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