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Review
. 2023 Aug 11:14:1239251.
doi: 10.3389/fimmu.2023.1239251. eCollection 2023.

"Outside-to-inside," "inside-to-outside," and "intrinsic" endogenous pathogenic mechanisms in atopic dermatitis: keratinocytes as the key functional cells involved in both permeability barrier dysfunction and immunological alterations

Yutaka Hatano  1 , Peter M Elias  2
Affiliations
Review

"Outside-to-inside," "inside-to-outside," and "intrinsic" endogenous pathogenic mechanisms in atopic dermatitis: keratinocytes as the key functional cells involved in both permeability barrier dysfunction and immunological alterations

Yutaka Hatano et al. Front Immunol. .

Abstract

Permeability barrier disruption has been shown to induce immunological alterations (i.e., an "outside-to-inside" pathogenic mechanism). Conversely, several inflammatory and immunological mechanisms reportedly interrupt permeability barrier homeostasis (i.e., an "inside-to-outside" pathogenic mechanism). It is now widely recognized that alterations of even a single molecule in keratinocytes can lead to not only permeability barrier dysfunction but also to immunological alterations. Such a simultaneous, bidirectional functional change by keratinocytes is herein named an "intrinsic" pathogenic mechanism. Molecules and/or pathways involved in this mechanism could be important not only as factors in disease pathogenesis but also as potential therapeutic targets for inflammatory cutaneous diseases, such as atopic dermatitis, psoriasis, and prurigo nodularis. Elevation of skin surface pH following permeability barrier abrogation comprises one of the key pathogenic phenomena of the "outside-to-inside" mechanism. Not only type 2 cytokines (e.g., IL-4, IL-13, IL-31) but also type 1 (e.g. IFN-γ), and type 3 (e.g., IL-17, IL-22) as well as several other inflammatory factors (e.g. histamine) can disrupt permeability barrier homeostasis and are all considered part of the "inside-to-outside" mechanism. Finally, examples of molecules relevant to the "intrinsic" pathogenic mechanism include keratin 1, filaggrin, and peroxisome proliferator-activated receptor-α (PPARα).

Keywords: PPAR alpha; allergic inflammation; atopic dermatitis; filaggrin; keratin 1; keratinocyte; permeability barrier dysfunction.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
“Outside to inside, back to outside” pathogenic mechanism via functional alterations in keratinocytes.
Figure 2
Figure 2
Examples of the “intrinsic” pathogenic mechanism via functional changes in keratinocytes.
See this image and copyright information in PMC

References

    1. Elias PM, Hatano Y, Williams ML. Basis for the barrier abnorMality in atopic dermatitis. outside-inside-outside pathogenic mechanisms. J Allergy Clin Immunol (2008) 121:1337–43. doi: 10.1016/j.jaci.2008.01.022 - DOI - PMC - PubMed
    1. Denda M, Wood LC, Emami S, Calhoun C, Brown BE, Elias PM, et al. The epidermal hyperplasia associated with repeated barrier disruption by acetone treatment or tape stripping cannot be attributed to increased water loss. Arch Dermatol Res (1996) 288:230–8. doi: 10.1007/BF02530090 - DOI - PubMed
    1. Nakahara T, Kido-Nakahara M, Tsuji G, Furue M. Basics and recent advances in the pathophysiology of atopic dermatitis. J Dermatol (2021) 48:130–9. doi: 10.1111/1346-8138.15664 - DOI - PubMed
    1. Kishibe M. Physiological and pathological roles of kallikrein-related peptidases in the epidermis. J Dermatol Sci (2019) 95:50–5. doi: 10.1016/j.jdermsci.2019.06.007 - DOI - PubMed
    1. Sakai T, Hatano Y, Matsuda-Hirose H, Zhang W, Takahashi D, Jeong SK, et al. Combined benefits of a PAR2 inhibitor and stratum corneum acidification for murine atopic dermatitis. J Invest Dermatol (2016) 136:538–41. doi: 10.1016/j.jid.2015.11.011 - DOI - PubMed

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