Beyond the Alarmin: Nuclear Interleukin-33 and Skin Barrier Dysfunction in Atopic Dermatitis
- 1Department of Dermatology, Ehime University Graduate School of Medicine, Ehime 791-0295, Japan
Abstract
Interleukin-33 (IL-33) belongs to the IL-1 superfamily and is defined by functional duality; it resides constitutively within barrier epithelial cell nuclei under homeostatic conditions but is released into the extracellular compartment, where it operates as an alarmin that initiates ST2-dependent type 2 inflammation, upon cellular damage. In atopic dermatitis (AD), IL-33 is markedly overexpressed in lesional keratinocytes, and its extracellular cytokine activity has long been regarded as the principal disease-relevant function. However, accumulating evidence indicates that nuclear IL-33 itself may play an active, receptor-independent role in keratinocyte biology. This review reconciled two apparently opposing paradigms of nuclear IL-33 whereby it acts as (1) a passive sequestration checkpoint that restrains alarmin activity in several cell types and (2) an active transcriptional regulator of the epidermal barrier in keratinocytes. We analyzed the proposed role of nuclear IL-33 as a putative intracellular hub of barrier dysfunction by summarizing how the major type 2 cytokines in AD (i.e., IL-4/IL-13, IL-31, and TSLP) converge on it to suppress barrier and differentiation genes, as well as filaggrin, loricrin, keratins, claudin-1, and antimicrobial peptide. We further explored the limited clinical efficacy of extracellular IL-33/ST2-targeting biologics in AD, compared with that of nuclear-IL-33-directed strategies, including topical trehalose, which are barrier-restorative, mechanistically targeted therapeutics. As this model derives largely from in vitro keratinocyte and three-dimensional skin studies, nuclear IL-33 should therefore be regarded as a putative, context-dependent cofactor whose direct chromatin action and in vivo relevance remain to be established.
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BibTeX
@article{muto2026beyond,
title = {{Beyond the Alarmin: Nuclear Interleukin-33 and Skin Barrier Dysfunction in Atopic Dermatitis}},
author = {Jun Muto},
journal = {Journal of Clinical Medicine},
year = {2026},
month = oct,
doi = {10.3390/jcm15207781},
url = {https://www.mdpi.com/2077-0383/15/20/7781},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond the Alarmin: Nuclear Interleukin-33 and Skin Barrier Dysfunction in Atopic Dermatitis
AU - Jun Muto
PY - 2026
DA - 2026/10/09
JO - Journal of Clinical Medicine
DO - 10.3390/jcm15207781
UR - https://www.mdpi.com/2077-0383/15/20/7781
AB - Interleukin-33 (IL-33) belongs to the IL-1 superfamily and is defined by functional duality; it resides constitutively within barrier epithelial cell nuclei under homeostatic conditions but is released into the extracellular compartment, where it operates as an alarmin that initiates ST2-dependent type 2 inflammation, upon cellular damage. In atopic dermatitis (AD), IL-33 is markedly overexpressed in lesional keratinocytes, and its extracellular cytokine activity has long been regarded as the principal disease-relevant function. However, accumulating evidence indicates that nuclear IL-33 itself may play an active, receptor-independent role in keratinocyte biology. This review reconciled two apparently opposing paradigms of nuclear IL-33 whereby it acts as (1) a passive sequestration checkpoint that restrains alarmin activity in several cell types and (2) an active transcriptional regulator of the epidermal barrier in keratinocytes. We analyzed the proposed role of nuclear IL-33 as a putative intracellular hub of barrier dysfunction by summarizing how the major type 2 cytokines in AD (i.e., IL-4/IL-13, IL-31, and TSLP) converge on it to suppress barrier and differentiation genes, as well as filaggrin, loricrin, keratins, claudin-1, and antimicrobial peptide. We further explored the limited clinical efficacy of extracellular IL-33/ST2-targeting biologics in AD, compared with that of nuclear-IL-33-directed strategies, including topical trehalose, which are barrier-restorative, mechanistically targeted therapeutics. As this model derives largely from in vitro keratinocyte and three-dimensional skin studies, nuclear IL-33 should therefore be regarded as a putative, context-dependent cofactor whose direct chromatin action and in vivo relevance remain to be established.
SN - 2077-0383
ER -