Mirikizumab

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Mirikizumab: Pathophysiology of Plaque Psoriasis: The Roles of IL-23 and IL-17a

IL-23 is an interleukin shown to have elevated expression in plaque psoriasis.

Detailed Information

Psoriasis vulgaris (plaque psoriasis) is a systemic disease of the immune system that manifests as a chronic inflammatory skin disease characterized by erythematous , well-demarcated patches covered in silver-white scales.1,2

There are multiple inflammatory cell types that are involved in the creating plaques like T-cells, dendritic cells, and macrophages which secrete cytokines including IL-23.2,3 In the presence of IL-23 and other stimulatory signals, naïve T cells in lymph nodes undergo differentiation and clonal expansion into effector TH17 cells.4 Subsequently, TH17 cells migrate to the dermis where they release IL-17a and other soluble mediators.5

IL-17a has multiple downstream and upstream effects. IL-17a drives the activation of keratinocytes, which at unregulated high levels, can cause hyperproliferation and aberrant differentiation. IL-17a can also increase expression pro-inflammatory mediators including IL-23, which contributes to survival of TH17 cells, triggering an amplified and prolonged immune response.2,3

The secretion of IL-17 and IL-22 from IL-23 stimulated cells are thought to promote hyperproliferation and aberrant differentiation of keratinocytes which form epidermal acanthosis, hyperkeratosis, and parakeratosis and diffuse hyperplasia.6 These processes result in the characteristic well-demarcated, scaly, elevated, erythematous plaques seen in plaque psoriasis.4

Overall, IL-23 and IL-17a play a pivotal function in generating and maintaining inflammatory response.3

The etiology of plaque psoriasis is complex and is not fully understood. The information is based on interpretation of the current literature and presents the currently accepted theory of pathogenesis of psoriasis. The information focuses on the IL-23 and IL-17a axis only, and does not preclude involvement of other immune factors within the pathophysiology of plaque psoriasis.1

Lilly is currently investigating IL-23 as a potential target for immune diseases, including psoriasis.

A video with a more detailed description of the mechanism of disease of plaque psoriasis can be accessed at:  https://www.kaltura.com/tiny/rcv15.7

References

1. Chiricozzi A, Romanelli P, Volpe E, et al. Scanning the immunopathogenesis of psoriasis. Int J Mol Sci. 2018;19(1):179. https://dx.doi.org/10.3390/ijms19010179

2. Girolomoni G, Strohal R, Puig J, et al. The roles of IL-23 and the IL-23/TH 17 immune axis in the pathogenesis and treatment of psoriasis. J Eur Acad Dermatol Venereol. 2017;31(10):1616-1626. https://dx.doi.org/10.1111/jdv.14433

3. Gaffen SL, Jain R, Garg AV, Cua DJ. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol. 2014;14(9):585-600. https://dx.doi.org/10.1038/nri3707

4. Boehncke W-H, Schön MP. Psoriasis. Lancet. 2015;386(9997):983-994. https://dx.doi.org/10.1016/S0140-6736(14)61909-7

5. Ma W-Y, Jia K, Zhang Y. IL-17 promotes keratinocyte proliferation via the downregulation of C/EBPα. Exp Ther Med. 2016;11(2):631-636. https://dx.doi.org/10.3892/etm.2015.2939

6. Suzuki E, Mellins ED, Gershwin ME, et al. The IL-23/IL-17 axis in psoriatic arthritis. Autoimmun Rev. 2014;13:496-502. http://dx.doi.org/10.1016/j.autrev.2014.01.050

7. Pathophysiology of Plaque Psoriasis: The Roles of IL-23 and IL-17a. Available at https://www.kaltura.com/tiny/rcv15. Accessed June 18, 2019.

Glossary

IL-17a = Interleukin-17a

IL-23 = Interleukin-23

Lilly = Eli Lilly and Company

TH17 = T helper 17 cells

Date of Last Review: April 03, 2019

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