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The Role of IL-13 in atopic dermatitis


Th2 cytokines, including IL-13, drive inflammation in atopic dermatitis affected skin1

In AD skin, overexpression of IL-13 leads to disruption of the skin barrier, increased risk of skin infections, further amplified inflammation, itch—and, in the chronic phase, remodeling and dermal thickening2-9

IL-4 can also mediate itch, but concentrations of IL-4 in AD skin are relatively low vs IL-13.7,12

Chart created by ADKeySuspect.com.au to show how IL-13 drives atopic dermatitis signs and symptoms

IL-13 acts directly on keratinocytes to:
  • Reduce expression of skin barrier proteins and lipids, thereby further disrupting the skin barrier, resulting in increased transepidermal water loss2-4
  • Down-regulate the expression of antimicrobial peptides, and thereby play a role in the dysbiosis of the skin, which is typically characterized by a strong colonization with Staphylococcus aureus and an increased risk of secondary skin infections5
  • Stimulate the secretion of chemokines and cytokines, which attracts more immune cells and amplifies the inflammatory response6
IL-13 can stimulate peripheral itch-sensory neurons, activating itch signaling and scratching.7

IL-13 down-regulates MMP-13 expression in human dermal fibroblasts and may thereby decrease collagen degradation, resulting in fibrosis with excess collagen deposition, as found in the thickened dermis of chronic lichenified AD skin lesions.8

Chronic itch sensations and associated scratching are components of a dynamic pathological process known as the itch-scratch cycle.9
  • Scratching exacerbates itch sensation through damage to the skin barrier, increasing exposure to allergens and microbes that may further amplify the inflammation
  • The epithelial stress response also releases cytokines that activate immune cells to promote inflammation
The released cytokines further stimulate peripheral itch-sensory neurons, resulting in itch signaling and further scratching.

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In AD skin, studies have found IL-13 to be expressed at higher levels than IL-4.13,14

References

  1. Bieber T. Interleukin-13: targeting an underestimated cytokine in atopic dermatitis. Allergy. 2019. doi:10.1111/all.13954.
  2. Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120(1):150-155.
  3. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126(3):332-337.
  4. Berdyshev E, Golvea E, Bronova I, et al. Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI Insight. 2018;3(4):e98006.
  5. Nomura I, Goleva E, Howell MD, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
    J Immunol. 2003;171(6):3262-3269.
  6. Purwar R, Werfel T, Wittmann M. IL-13-stimulated human keratinocytes preferentially attract CD4+CCR4+ T cells: possible role in atopic dermatitis. J Invest Dermatol. 2006;126(5):1043-1051.
  7. Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017;171(1):217-228.e13.
  8. Moriya C, Jinnin M, Yamane K, et al. Expression of matrix metalloproteinase-13 is controlled by IL-13 via PI3K/Akt3 and PKC-δ in normal human dermal fibroblasts.
    J Invest Dermatol. 2011;131(3):655-661.
  9. Mack MR, Kim BS. The itch-scratch cycle: a neuroimmune perspective. Trends Immunol. 2018;39(12):980-991.
  10. Bao K, Reinhardt RL. The differential expression of IL‐4 and IL‐13 and its impact on type‐2 immunity. Cytokine. 2015;75(1):25‐37.
  11. Salimi M, Barlow JL, Saunders SP, et al. A role for IL‐25 and IL‐33‐driven type‐2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013;210(13):2939‐2950.
  12. Tsoi LC, Rodriguez E, Degenhardt F, et al. Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J Invest Dermatol. 2019;139(7):1480-1489.
  13. Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295(11):459-464.
  14. Koppes SA, Brans R, Ljubojevic Hadzavdic S, Frings-Dresen MH, Rustemeyer T, Kezic S. Stratum corneum tape stripping: monitoring of inflammatory mediators in atopic dermatitis patients using topical therapy. Int Arch Allergy Immunol. 2016;170(3):187-193.