Psoriasis is more than a dermatological disorder. It is a chronic immune-mediated disease in which genetically susceptible individuals develop cutaneous inflammation and keratinocyte hyperproliferation (Nestle et al., 2009; Boehncke & Schön, 2015).

Psoriasis is associated with epidermal thickening and keratinocyte hyperproliferation. As a result, the skin becomes inflamed and has raised plaques with silvery scales (as shown in the figure below), which can cover large areas of the body (Nestle et al., 2009; Boehncke & Schön, 2015; Palfreeman et al., 2013).

Pathophysiology of psoriasis

Clinical course 

The clinical course of psoriasis can be divided into two stages: an initiation phase and a maintenance phase that perpetuates the inflammatory state (Sabat et al., 2007). This separation may be helpful when considering treatments that act in the trigger phase and those that block the self-perpetuating cycle of inflammation (Diani et al., 2015).

The histological features of psoriasis include epidermal (keratinocyte) hyperplasia, leukocyte infiltrates and an increased number of leaky vessels in the dermis of the skin (see Figure 3). Recently, lymphoid-like tissues have also been identified in the psoriatic plaques (Diani et al., 2015).

Psoriasis pathophysiology

Figure 3. Psoriasis pathophysiology (adapted from Palfreeman et al., 2013).

Initiation phase

An interplay between environmental and genetic factors facilitates disease-initiating events and the initiation of the complex and dynamic psoriatic cascade within skin and immune cells (Nestle et al., 2009).

The histological features of cutaneous psoriasis are due to the interactions between T cells, dendritic cells and keratinocytes, giving rise to sustained inflammation in the skin (Figure 4) (Becher et al., 2012; Diani et al., 2015). It is now well accepted that T cells, particularly T helper (Th) 17 lymphocytes, play an important role as effector cells in the pathogenesis of psoriasis (Büchau et al., 2007; Sabat et al., 2007).

Early events in psoriasis involve the following steps (Becher et al., 2012):

  • People who are genetically predisposed to develop psoriasis (such as those with HLA-C*06:02, the main psoriasis risk allele) seem to show melanocyte-specific autoimmunity (Prinz, 2017). In these patients, skin insults activate dendritic cells (DCs) through pattern recognition receptors (PRRs) or cytokines interleukin 1 (IL-1), TNFα and IL-36. Meanwhile, a subset of DCs called plasmacytoid dendritic cells (pDCs) that typically mount a type 1 interferon (IFN) response to viral/microbial DNA have also been implicated in psoriasis
    • Research has suggested that combination of self-DNA with an antimicrobial peptide called LL37 (also called CAMP) can lead to a pDC-mediated immune response against self-DNA and subsequent activation of T cells. Infiltration of psoriatic skin has been observed for pDCs and it has been hypothesised that skin damage and subsequent release of self-DNA can lead to local pDC activation and drive autoimmunity and inflammation in psoriasis (Lande et al., 2007)
  • Activated DCs produce IL-23, which activates T cells and innate lymphoid cells (ILCs) to produce TNFα, IL-17 and IL-22
    • IL-22 induces keratinocyte hyperproliferation
    • TNFα and IL-17 activate DCs and keratinocytes, leading to up-regulation of adhesion molecules by the skin epithelium, angiogenesis and chemokine production
    • IL-17–induced chemokines CXCL1 and CXCL8 which recruit neutrophils
  • IL-17R engagement by keratinocytes leads to production of CCL20, which attracts more circulating CCR6+ γδ T cells and ILCs. This escalates into a self-amplifying inflammatory loop that can also be mediated by the adaptive immune system (Becher et al., 2012) 
Initiation of psoriasis

Figure 4. Initiation of psoriasis (adapted from Becher et al., 2012).
CCL20, chemokine ligand 20; CCR6, chemokine receptor 6; CLA, cutaneous lymphocyte antigen; CXCL, chemokine (C-X-C motif) ligand; IFN-γ, interferon-gamma; IL, interleukin; ILC, innate lymphoid cells; PRRs, pattern recognition receptors; RORγt, retinoid-related orphan receptor γt; TH, T helper cell; TNF-α, tumour necrosis factor-alpha.

Maintenance phase

Key processes during disease maintenance involve ‘cross talk’ between epithelial and immune cells and the transition from innate to adaptive immunity as described in Figure 5 (Nestle et al., 2009).

Maintaining psoriasis – transition from adaptive to innate immunity

Figure 5. Maintaining psoriasis – transition from adaptive to innate immunity (adapted from Nestle et al., 2009).
CCL, chemokine ligand; CXCL, chemokine (C-X-C motif) ligand; IFN-α, interferon-alpha; IFN-γ, interferon-gamma; IL, interleukin; TH, T helper cell; TNF-α, tumour necrosis factor-alpha.

The cells and cytokines involved in the perpetuation/maintenance of psoriasis represent key therapeutic targets (Sugiyama et al., 2005; Nestle et al., 2009; Chandrakumar et al., 2014; Boehncke & Schön, 2015; Diani et al., 2015).

  • Secretion of IL-23 and IL-12 by DCs within the lymph nodes induces naïve T cells to differentiate into Th17 or Th1 cells, respectively
  • T cells migrate to skin and produce further cytokines (IFNγ, IL-17 and IL-22) which drive epidermal cell proliferation

These cytokines lead to over-activity of keratinocytes and this leads to the release of cytokines and chemokines that continue to recruit and activate inflammatory cells. The balance between regulatory and effector functions is lost and regulatory T cells (Tregs) are unable to control ongoing inflammation.

Cytokines in psoriasis

Cytokines are small polypeptides (8–80 kDa) produced in response to antigens, microorganisms or other non-infectious stimuli that can regulate immune and inflammatory reactions (Brotas et al., 2012). 

A large number of inflammatory cytokines are elevated in psoriasis and, in a subset of these cytokines, their serum concentrations correlate with disease severity (Baliwag et al., 2015).

The combined effects of the cytokines found in psoriasis lesions may explain most of the clinical features of psoriasis: (Baliwag et al., 2015).

  • Keratinocyte hyperproliferation 
  • Increased neovascularisation 
  • Skin inflammation 

An understanding of which cytokines play a pivotal role in the disease process has revealed potential therapeutic targets, and several cytokines have been successfully targeted, revolutionising treatment (Baliwag et al., 2015).

Find out more about the challenge of targeted treatments for psoriasis from Professor Andrew Blauvelt.


TNFα is the most studied psoriasis cytokine due to its increased expression in skin lesions/serum/synovial fluid of psoriasis/PsA and the therapeutic efficacy of its specific inhibitors (fusion proteins, monoclonal antibodies) (Brotas et al., 2012).

Tumour necrosis factor-alpha (TNFα) is an important Th1 pro-inflammatory cytokine that is up-regulated in psoriasis (Brotas et al., 2012; Lowes et al., 2014). It is often described as a ‘primary cytokine’ since it can independently initiate a number of mechanisms capable of triggering inflammation.

What TNFα-mediated mechanisms trigger inflammation?

TNFα has been demonstrated to be involved in (Brotas et al., 2012; Lowes et al., 2014):

  • Endothelial activation
  • Immunocyte recruitment
  • Immunocyte-keratinocyte recruitment
  • Amplification of inflammation
  • Keratinocyte hyperproliferation

Where is TNFα detected? TNFα is present in psoriatic dermal CD45(+)HLA-DR(+) leukocytes consisting of CD11c(+) dendritic cells and CD163(+) macrophages. In peripheral blood, an increase in the TNFα-producing myeloid subsets of CD14(-) 6-sulfo-LacNac(+) dendritic cells and CD14(+)CD16(+) "intermediate" monocytes was observed in psoriasis compared with healthy control subjects. Detectable levels of TNFα are not present in other cells, including keratinocytes or T cells, making these cell types unlikely targets of TNFα blockers (Brunner et al., 2013).

What causes the reduction in inflammation during anti-TNFα therapy?

The decrease in tissue inflammation during anti-TNFα therapy is not due to immediate killing of TNFα-producing cells but rather results from a rapid downregulation of the pathogenic IL-12/IL-23-driven immune response (Brunner et al., 2013).


The cytokine family IL-17 plays a central role in the promotion of an inflammatory response, activating dendritic cells to release a variety of cytokines and chemokines to promote neutrophil chemotaxis, enhancing the production of antimicrobial peptides, while also stimulating fibroblast release of vascular endothelial growth factor (VEGF) to support angiogenesis and endothelial cell proliferation (Amatya et al., 2017; Roman & Chiu, 2017).

The IL-17 family of cytokines consists of six members (IL-17A to IL-17F), which exist as a combination of homo- and heterodimers. The most influential cytokine in the family is believed to be IL-17A, which is found as a homodimer or as a heterodimer with IL-17F, while IL-17C, E and F also function as homodimers.

The IL-17 family of cytokines and their associated receptors

IL-17 cell surface receptors

Further complexity is added to the IL-17 cytokine family by the presence of five cell surface receptors (IL-17-RA–RE). IL-17RA forms heterodimers with IL-17RB, IL-17RC, and IL-17RE with the IL-17RA/RC heterodimer capable of binding both IL-17A and IL-17F. Meanwhile, IL-17E has been shown to bind to the IL17-RA/RB heterodimer and IL-17C binding to the IL-17RA/RE heterodimer (Amatya et al., 2017; Roman & Chiu, 2017).

IL-17 and psoriasis

IL-17 sustains inflammation in psoriatic plaques by stimulating production of antimicrobial peptides leading to the recruitment of inflammatory cells, enhanced proliferation of keratinocytes and inhibition of keratinocyte differentiation (Soler et al., 2011; Lowes et al., 2014; Diani et al., 2015).

IL-17A as a therapeutic target

The role of IL-17A in the pathogenesis of psoriasis and as targets for the IL-17 antagonists secukinumab and ixekizumab is described in Figure 6 (Lønnberg et al., 2014). These IL-17A antagonists have shown promising activity in clinical studies, supporting the role of IL-17A in disease pathogenesis (Langley et al., 2014; Blauvelt et al., 2015; Mrowietz et al., 2015; Paul et al., 2015a; Reich et al., 2015a; Thaci et al., 2015; Gottlieb et al., 2017). Indeed, secukinumab has been shown to decrease keratinocyte activation and improve keratinocyte differentiation in skin biopsy samples from psoriasis patients investigated using histology and transcriptomics (Krueger et al., 2019).

Clinical and immunological response patterns to the anti-IL-17A antibody secukinumab in patients with moderate-to-severe psoriasis are indicative of a neutrophil-keratinocyte axis in psoriasis involving neutrophil-derived IL-17 (Reich et al., 2015b).

IL-17 receptor as a therapeutic target

Brodalumab disrupts IL-17 signalling by targeting the IL-17 receptor itself, rather than binding the IL-17 cytokine. This means brodalumab blocks the signalling of not just the IL-17A cytokine, but also IL-17F, the IL-17A/F heterodimer and IL-17E (also called IL-25).

In addition, large amounts of IL-17C are produced in keratinocytes (production in psoriasis is about 100 times greater than IL-17A), inhibiting IL-17C may therefore be beneficial for psoriasis patients. To date, brodalumab is the only anti-IL-17 treatment that affects IL-17C, since it blocks the shared IL-17 receptor (Galluzzo et al., 2019).

IL-17A in the pathogenesis of psoriasis, and targets for brodalumab, secukinumab, and ixekizumab

Figure 6. IL-17A in the pathogenesis of psoriasis, and targets for brodalumab, secukinumab, and ixekizumab (adapted from Lønnberg et al., 2014).
IFN-γ, interferon-gamma; NK, natural killer; Tc, cytotoxic T cell; TGF-β, transforming growth factor-beta; Th, T helper cell; TNFα, tumour necrosis factor-alpha.


IL-23 is a heterodimeric cytokine with two subunits (p19 and p40) that is highly expressed in psoriatic skin lesions. IL-23 – which is produced mainly by dendritic cells and macrophages – has emerged as a key pro-inflammatory cytokine, driving autoimmunity and the development of IL-17A-producing Th17 cells (Di Meglio & Nestle, 2010; (Haugh et al., 2018; Fotiadou et al., 2018).

Essentially, IL-23 activates and maintains the Th17 pathway that drives psoriasis (Fotiadou et al., 2018). IL-23 modulates immune responses mediated by type 1-polarised T cells in peripheral tissues. Patients with psoriasis show increased numbers of type 1-polarised T cell in lesions and their peripheral circulation (Haugh et al., 2018). 

IL-23 triggers the differentiation of Th17 and Th22 cells. These, in turn, upregulate the inflammatory cascade that underlies the development of psoriatic lesions. For instance, Th17 cells produce IL-17, IL-22, IL-21 and TNFα, which induces a self-amplifying inflammatory response in the keratinocytes of pre-psoriatic skin (Fotiadou et al., 2018; Haugh et al., 2018).

IL-17 recruits leucocytes to the lesion (Haugh et al., 2018). Eosinophils, mast cells, basophils and epithelial cells produce IL-25 (also known as IL-17E). IL-25 signals through IL-17 receptors to augment Th2 cell immune responses (Sakkas et al., 2019). In the ‘IL-23/Th17 axis’ model of psoriasis, Th17 cells interact with skin-resident cells contributing to the psoriatic disease phenotype. 

As mentioned, IL-23 is a heterodimer – the cytokine consists of two subunits. The P19 subunit is specific to IL-23. IL-12 and IL-23 both contain p40 (Haugh et al., 2018; Fotiadou et al., 2018). Drugs that selectively target the IL-23p19 offer a new biologic treatment for moderate–to–severe psoriasis (Fotiadou et al., 2018).

IL-23 in psoriasis

Ustekinumab, which inhibits IL-12 and IL-23, and the IL-23 inhibitors, guselkumab, mirikizumab, risankizumab and tildrakizumab, have demonstrated efficacy in psoriasis (Langley et al., 2015; Blauvelt et al., 2017a; Reich et al., 2017a; Gordon et al., 2018b; Gisondi et al., 2019).

Find out more about treatment selection and head-to-head studies with IL-17 and IL-23 inhibitors from Professor Andrew Blauvelt.


Interferon gamma (IFNγ) also plays a role in the pathogenesis of psoriasis, and is thought to activate antigen-presenting cells, lead to the production of IL-23 from dendritic cells and favour IL-17-producing cell recruitment and activation (Lowes et al., 2014; Diani et al., 2015). Biologics targeting TNF can cause skin lesions that resemble psoriasis - an adverse event known as paradoxical psoriasis. Type 1 interferons seem to drive paradoxical psoriasis by inducing autoimmune reactions to T cells (Mylonas and Conrad, 2018). 


IL-1 is a proinflammatory cytokine principally expressed by keratinocytes and involved in the homeostasis of the skin. Various activating, promoting and inhibitory agents are involved in the regulation of IL-1 signalling including different IL-1 isoforms, competitive inhibitors and decoy receptors. These all function together to prevent excessive inflammatory responses. Typically, IL-1 signalling is active during stress, inflammatory and immune responses, however, various factors have been shown to result in IL-1 pathway dysregulation, including (Gómez-Garcia et al., 2018):

  • Viral infection
  • Ultraviolet a and b exposure
  • Chemical exposure
  • Skin barrier integrity

Dysregulation of IL-1 has been associated with the development of a variety of chronic, autoinflammatory skin diseases, including psoriasis. Recent data suggests that IL-1β-IL-1R signalling may contribute to this process via regulation of IL-17 producing cells within the skin, in addition to stimulation of keratinocytes, resulting in amplification of the inflammatory cascade (Cai et al., 2019). IL-1R signalling appears to correlate with psoriasis disease progression and treatment response (Cai et al., 2019).


A member of the IL-20 family of cytokines, IL-22 is produced by Th17 and Th22 cells and has been implicated in several inflammatory diseases including systemic lupus erythematosus, rheumatoid arthritis and psoriasis. IL-22 acts as a homodimer binding to a receptor complex of IL-10R2 and IL-22R1 resulting in activation of members of the signal transducer and activator of transcription (STAT) family of transcription factors (Hao, 2014; Chiricozzi et al., 2018).

Expression of the IL-22 receptor is increased in psoriatic lesional skin and IL-22 signalling in psoriasis has been linked to enhanced keratinocyte migration, increased epidermal thickness, reduced keratinocyte differentiation and higher expression levels of various molecules such as chemokines and chemoattractants, although not as strongly as IL-17 (Chiricozzi et al., 2018). IL-22 may collaborate with other soluble factors and cells together forming inflammatory circuits that become pathologically amplificated in psoriasis. Targeting IL-22 may be a promising potential therapeutic for plaque psoriasis (Wawrzycki et al., 2019).


A member of the IL-1 family of cytokines, IL-36 comprises IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by both TNF-α and IL-17. In contrast, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36 (Madonna et al., 2019).

Chemokines in psoriasis

CXC chemokine ligand 1 (CXCL1) and CXCL8 are neutrophil chemoattractants that are produced by keratinocytes in response to IL-17 and IL-22 signalling. The cytokine-mediated upregulation of chemokines, including CXCL1 and CXCL8, has been shown to promote the recruitment of neutrophils to psoriatic lesions (Reich et al., 2015b). The presence of neutrophils may be an important driver of the induction phase of psoriasis due to their secretion of proinflammatory cytokines, including IL-17, and the formation of neutrophil extracellular traps, which contain high-levels of self-DNA/nucleic acids (Steffen et al., 2018).

Click here to view the Treatment section for further details on TNFα, IL-17, IL-12 and IL-23 inhibitors.

Trigger factors for psoriasis

Common psoriasis trigger factors in psoriasis

Figure 7. Common psoriasis trigger factors (Lowes et al., 2014; Marshall et al., 2015).

Emotional stress

Between 26–88% of patients with psoriasis reported stress in a meta-analysis of the relationship between stress and psoriasis (Rousset & Halioua, 2018).

Research suggests that the activation of corticotropin-releasing hormone in stress provokes the degranulation of mast cells, which in turn release pro-inflammatory cytokines, exacerbating psoriasis (Theoharides & Cochrane, 2004; Harvima et al., 2008; Evers et al., 2010; Heller et al., 2011;). It has also been suggested that stress can modify the permeability of the epidermal barrier, which maintains the inflammatory skin reaction (Elias et al., 1999; Garg et al., 2001).

Continuous exposure to stress could also be a trigger for psoriasis, as one study found flares to be more frequently reported in patients with psoriasis who were experiencing permanently high levels of stress, particularly related to stressful family events (Evers et al., 2010).


The association between bacterial (streptococcal) throat infection and psoriasis is thought to be due to activation of T cells in the tonsils, which then move to the skin, where CD8+ T cells cross-recognise keratin determinant on keratinocytes, and CD4+ T cells interact with dendritic cells and amplify the response, with IL-23 induced IL-17 responses giving rise to the clinical psoriasis (Diani et al., 2015).

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