Atopic dermatitis mechanism and therapies (Homo sapiens)

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Atopic dermatitis (AD), also known as atopic eczema, arises from a complex interplay of genetic susceptibility and environmental triggers that disrupt the skin barrier. This dysfunction is exacerbated by alterations in the skin microbiome—particularly a reduction in Staphylococcus epidermidis and an overgrowth of Staphylococcus aureus—which increase the skin's vulnerability to external allergens.

Keratinocytes, in response to this disruption, release epithelial-derived cytokines such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33. These cytokines promote type 2 immune responses by activating group 2 innate lymphoid cells (ILC2s), T helper 2 (Th2) cells, and T follicular helper 2 (Tfh2) cells. These lymphocytes, stimulated by activated Langerhans cells (LCs) and inflammatory dendritic epidermal cells (IDECs), subsequently secrete IL-4, IL-5, and IL-13.

IL-4 and IL-13 signal through type I (IL-4Rα / CD132) and type II (IL-4Rα / IL-13Rα1) receptors expressed on B cells, keratinocytes, and sensory neurons, activating the JAK-STAT signaling pathway. Tfh2 cells promote class switching to IgE in B cells, enhancing mast cell and basophil activation via FcεRI. Concurrently, IL-4 and IL-13 reduce the production of antimicrobial peptides (AMPs), such as human β-defensin 3, in keratinocytes, further impairing the skin’s defense.

Pruritus (itch) is driven by IL-4, IL-13, IL-31, IL-33, and TSLP, which stimulate sensory neurons and perpetuate the itch-scratch cycle. Type 2 cytokines also worsen dysbiosis of the skin microbiota, while IL-5 recruits eosinophils, fueling ongoing inflammation.

Several immunotherapeutic agents have been developed to target these pathways:

• Dupilumab (brand name Dupixent) blocks IL-4Rα, inhibiting both type I and type II receptor signaling.

• Tralokinumab (Adbry, Adtralza) neutralizes IL-13.

• Nemolizumab (Nemluvio) targets the IL-31 receptor to reduce itch.

• Upadacitinib (Rinvoq) and abrocitinib (Cibinqo) are oral selective JAK1 inhibitors.

• Baricitinib (Olumiant) inhibits both JAK1 and JAK2.

• Topically, ruxolitinib (Jakafi, Jakavi, Opzelura; a JAK1/2 inhibitor) and delgocitinib (Corectim, a pan-JAK inhibitor) are approved for the treatment of AD.

Inspired by Figure 2 in [Song et al. (2022)](https://pmc.ncbi.nlm.nih.gov/articles/PMC8901701/).