Mechanism of disease

Our understanding of the complex immunopathogenic mechanisms driving psoriasis continues to be illuminated. Increased clarity on the interactions between keratinocytes and immunes cells within the immune circuit sheds light on the cycle of inflammation.

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A DEEPER LOOK AT THE IL-17/23 AXIS THAT IS CENTRAL TO PSORIASIS PATHOGENESIS

Psoriasis is a manifestation of an inflammatory cascade in response to stress or genetic triggers. These triggers correlate with increased infiltration of immune cells in the skin, including dendritic cells, T cells, and neutrophils.1

Initially, activated dendritic cells secrete many inflammatory cytokines, including IL‑23, which stimulate T17 cells to produce additional cytokines, IL‑17A and IL‑17F.1

The immune cells also secrete TNFα, which acts in synergy with the other proinflammatory cytokines to activate keratinocytes, producing additional proinflammatory mediators.1

THE ACTIVATED KERATINOCYTE POWERS AN INFLAMMATORY FEEDBACK AMPLIFICATION LOOP

Activated keratinocytes secrete cytokines and chemokines which perpetuate the inflammatory feedback amplification loop. IL‑17C further activates T17 cells, and IL-36 stimulates dendritic cells.2–4 Chemokines, such as CCL20, IL‑8, and CXCL1, are secreted by activated keratinocytes to attract immune-mediating cells, which provide additional sources of IL‑17A and IL‑17F independent of IL-23, as well as proteases that activate IL‑36.1,3,5 This persistent inflammatory feedback loop results in keratinocyte hyperproliferation and leads to the clinical symptoms of pain, itching, and skin plaques.1,3,6,7

Cytokines that power the psoriasis inflammatory circuit

Click on each cytokine to learn more.

TNFα PRODUCED BY DENDRITIC CELLS AND T17 CELLS ACTIVATES KERATINOCYTES

TNFα was one of the first cytokines to be defined as pathogenic in psoriasis. TNFα is produced by various immune cells, including dendritic cells, and also keratinocytes themselves. It stimulates inflammation and hyperproliferation of keratinocytes in psoriatic lesions.1

IL-23 PRODUCED BY DENDRITIC CELLS MODERATES THE T-CELL PATHWAY

IL-23 plays a key role in the T-cell pathway and is essential for the differentiation of T17 cells.8

Internal or external triggers activate dendritic cells to produce IL-23. This is indicated by increased levels of the IL-23–characterizing p19 and p40 subunit mRNA in lesional skin compared with non‑lesional skin (p19 and p40 mean increase of 22‑fold and 12‑fold, respectively).9

The IL-23/17 interplay is known to be at the core of psoriasis immunopathology.3 Research shows that, as a result of IL‑23 mediation, additional IL‑17 subtypes become elevated in the skin. Importantly, IL‑23 blockade does not completely inhibit IL‑17 production, as other sources of IL‑17 may be present.10

IL-17A AND IL-17F ARE PRODUCED BY THE INNATE AND ADAPTIVE IMMUNE SYSTEM

T17 cells secrete IL-17A and IL-17F, both of which are present as homodimers and heterodimers and play critical overlapping roles in psoriasis pathogenesis.1

Most IL-17 family subtype cytokines are elevated in psoriasis. The abundance of IL-17F in psoriatic skin compared to non-lesional skin is more elevated than IL-17A. Both are important proinflammatory cytokines in the pathogenesis of psoriasis.1,11,12

The expression of T17 cells both in circulation and in lesional skin has been shown to correlate clinically with the severity of psoriasis.1 IL-17A and IL-17F are produced by not only T17 cells but also cells of the innate-like immune system, such as γδ T cells and ILC3.8,10

T17 FEEDBACK AMPLIFICATION: IL-17C

Activated keratinocytes secrete IL-17C, which stimulates T17 cells to propagate the cycle of inflammation in psoriasis.2,13

IL-17C receptor are found on T17 cells. This receptor is a dimer comprising IL-17RE and IL-17RA. In T17 cells, IL-17RE gene expression was detected at a higher level than IL-23R, a receptor with known functional importance in these cells. Whereas IL-17RA is present in other receptor dimers, IL-17RE is unique to the IL-17C receptor; therefore, IL-17RE expression is a useful indicator of which cells are targeted by IL-17C.2,14

DENDRiTIC CELLS FEEDBACK AMPLIFICATION: IL‑36

IL-36 production by activated keratinocytes leads to further dendritic cell stimulation.3,4

In vitro assays of human cells have shown that IL‑36? and IL‑36γ are produced by keratinocytes after stimulation with IL‑17A, TNFα, and other proinflammatory mediators. Elevated levels of IL‑36 cytokines are then able to activate dendritic cells, as evidenced by the presence of CD83 and CD86 markers.3,4

NEUTROPHILS FEEDBACK AMPLIFICATION: CHEMOKINES (CXCL1, IL‑8, AND CCL20)

Activated keratinocytes in psoriatic lesions produce chemokines (e.g. CXCL1, IL‑8, CCL20) that recruit neutrophils and other immune cells to the site of inflammation.1

These recruited neutrophils have the potential to secrete additional IL‑17A and IL‑17F that can further activate keratinocytes.5,10

Immune cell migration in response to stimulation with IL‑17A and IL‑17F was observed in vitro. Following stimulation, migration by T cells and monocytes was observed, but most notable was the increased number of migrating neutrophils.15-17

A deeper look at the IL-17/23 axis shows that additional proinflammatory cytokines such as TNFα, IL-23, IL-17A, and IL-17F are all key cytokines found in psoriatic lesions1

The activated keratinocytes power an inflammatory feedback amplification loop1,3

Collectively, these pathways of inflammatory feedback amplification loop can lead skin plaques that cause clinical symptoms of pain, itching, and burning sensations1,3,6,7

unmet need

The complex pathogenesis of psoriasis is materialized in the form of psoriatic plaques, causing clinical symptoms that may severely impact the patient quality-of-life.

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