The IL-23 and Th17 Axis: The Immune Circuit Behind Psoriasis

Key Takeaways:

• In psoriasis, inflammatory dendritic cells in the skin release IL-23 and IL-12, which activate IL-17-producing T cells along with Th1 and Th22 cells; their cytokines, IL-17, interferon-gamma, TNF, and IL-22, act on keratinocytes to amplify the inflammation.
• IL-17 signaling in keratinocytes sets up a self-amplifying “feed-forward” loop that drives epidermal thickening, rapid skin-cell proliferation, and recruitment of white blood cells into the plaque.
• In two phase 3 trials of an antibody against the IL-23 p19 subunit, about 75 percent of patients with moderate-to-severe plaque psoriasis reached 90 percent skin clearance at week 16, compared with 2 to 5 percent on placebo and 42 to 48 percent on an older IL-12/23 blocker.

October 29 is World Psoriasis Day, and the most useful thing to understand about the disease is that it is not a problem of dry or irritated skin. Psoriasis is the best-understood T cell-mediated disease in human medicine, and the role of IL-23 in psoriasis sits at the center of a defined immune circuit. In people with an inherited susceptibility, and several genetic regions tied to immune signaling have been mapped, a trigger such as injury, infection, or stress activates a population of inflammatory dendritic cells in the dermis. These cells release two related messengers, IL-23 and IL-12. IL-23 is the key one. It sustains and expands a class of T cells that produce IL-17, often called Th17 cells, while IL-12 and related signals recruit Th1 and Th22 cells that make interferon-gamma, TNF, and IL-22. That cytokine mixture lands on the keratinocytes, the cells that build the outer skin, and changes their behavior. Under this signal, keratinocytes divide rapidly, fail to mature properly, and pile up into the thick, silvery scale of a plaque, while the dermis beneath fills with dilated blood vessels and immune cells. The redness, the thickness, and the scale are all downstream readouts of one upstream conversation between dendritic cells and T cells.

What turns a flare into a chronic plaque is that the circuit amplifies itself. IL-17 does not simply tell keratinocytes to grow; it induces them to produce their own chemical signals, including chemokines that pull in neutrophils, T cells, and dendritic cells, and antimicrobial peptides such as LL-37, which bind fragments of the body’s own DNA and RNA and further activate dendritic cells. The result is a feed-forward loop: IL-17 activity in pre-psoriatic skin drives epidermal thickening, rapid cell proliferation, and recruitment of white blood cells, which in turn release more of the cytokines that started the process. For decades, treatment worked around this circuit rather than through it, with broad immunosuppressants and later with blockers of TNF, a cytokine that sits in the loop but also has many unrelated jobs. The IL-23 and IL-17 model made a sharper prediction: cut the axis itself and the plaque should collapse. The trials bore it out. In two phase 3 trials enrolling more than 2,000 patients, an antibody against IL-17A produced a 75 percent improvement in skin severity scores at 12 weeks in 77 to 82 percent of patients on the higher dose, compared with about 5 percent on placebo and 44 percent on an older TNF blocker, validating IL-17A as a therapeutic target.

Why does blocking IL-23 in psoriasis work so well?

Blocking IL-23 acts one step further upstream, removing the signal that keeps IL-17-producing cells alive rather than mopping up their product. In two replicate phase 3 trials involving nearly 1,000 adults with moderate-to-severe plaque psoriasis, an antibody against the p19 subunit unique to IL-23 brought about 75 percent of patients to 90 percent clearance at week 16, compared with 2 to 5 percent on placebo and 42 to 48 percent on an older antibody that blocks IL-12 and IL-23 together. That is a remarkable result for a disease once managed with tar and ointment. It deserves the same honest framing as any other treatment, though. These medicines are designed for moderate-to-severe disease, not for a few limited patches, and in the IL-17 trials infections were more common than with placebo, at rates similar to the older TNF blocker. Choosing among the classes depends on whether joints are involved, on other conditions such as inflammatory bowel disease, and on individual history, which makes it a decision for each person and their clinician rather than a one-size recommendation. The larger lesson of World Psoriasis Day is the one this circuit teaches: psoriasis is a systemic immune disease with a known wiring diagram, and understanding that wiring is what turned it from something people learned to hide into something that can very often be controlled.

References:

1. Lowes, M. A., Suárez-Fariñas, M., & Krueger, J. G. (2014). Immunology of psoriasis. Annual Review of Immunology, 32, 227-255.
2. Hawkes, J. E., Chan, T. C., & Krueger, J. G. (2017). Psoriasis pathogenesis and the development of novel targeted immune therapies. The Journal of Allergy and Clinical Immunology, 140(3), 645-653.
3. Langley, R. G., Elewski, B. E., Lebwohl, M., Reich, K., Griffiths, C. E., Papp, K., et al. (2014). Secukinumab in plaque psoriasis: Results of two phase 3 trials. The New England Journal of Medicine, 371(4), 326-338.
4. Gordon, K. B., Strober, B., Lebwohl, M., Augustin, M., Blauvelt, A., Poulin, Y., et al. (2018). 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. The Lancet, 392(10148), 650-661.