A putative pharmacodynamic ceiling for topical corticosteroids in atopic dermatitis: a steroid-primed inflammasome and caspase-1–mediated glucocorticoid receptor cleavage
4 affiliations
- 1Department of Microbiology and Immunology, Seoul National University College of Medicine
- 2Department of Biomedical Sciences, Seoul National University College of Medicine
- 3Wide River Institute of Immunology, Seoul National University College of Medicine
- 4Shaperon Inc.
Abstract
Background: Topical corticosteroids (TCS) remain the first-line anti-inflammatory treatment for mild-to-moderate atopic dermatitis (AD), yet continuous use is constrained by cutaneous toxicity, rebound phenomena and topical steroid withdrawal (TSW).
Objective: This article proposes a mechanistic model in which glucocorticoids prime a cutaneous inflammasome axis that both sustains relapse risk and progressively reduces glucocorticoid receptor (GR) availability through caspase-1-mediated cleavage.
Methods: A narrative, hypothesis-generating synthesis integrated clinical trials of proactive maintenance and non-steroidal topicals with mechanistic data on glucocorticoid signaling, NLRP3 inflammasome biology, purinergic P2X7 receptor (P2X7R) pathways, keratinocyte-immune crosstalk and GR regulation.
Hypothesis: TCS are among the most effective topical agents for AD, but prolonged use is associated with steroid-associated rosacea-like dermatitis and TSW, iatrogenic phenotypes with no non-steroidal counterpart. Residual relapse under proactive maintenance is of comparable magnitude whether maintenance is steroidal or non-steroidal and is therefore taken here as the clinical problem to be solved. Glucocorticoids can transactivate NLRP3 in myeloid cells and induce CCL20 and TLR2 in keratinocytes, increasing inflammasome sensor abundance and sensitivity. On tapering or withdrawal, under continued subclinical type 2 inflammation, barrier disruption, microbial colonization and LL-37 and ATP release, the primed P2X7R-NLRP3 axis may discharge. In leukemia cells, active caspase-1 cleaves GR, reducing receptor occupancy at glucocorticoid-responsive elements and conferring steroid resistance; analogous activity in skin would be expected to narrow progressively the GR pool available to subsequent TCS doses.
Conclusions: The model reframes steroid-associated rosacea-like dermatitis and TSW as predictable discharges of a pharmacologically primed inflammasome rather than as idiosyncratic toxicity, with the limit on prolonged TCS use proposed to be set by P2X7R-NLRP3-caspase-1-GR interactions. It favors an add-on strategy co-administered with TCS from induction onward, targeting inflammasome assembly or caspase-1 activity to preserve GR integrity and prolong safe first-line steroid use, rather than relying on second-line non-steroidal substitution alone. No new experiments, patient-level analyses or meta-analyses are presented; prospective studies should quantify inflammasome activation, extracellular ATP and GR cleavage in human skin across the induction, maintenance, tapering and withdrawal phases of TCS therapy.
Related
- Phage intervention improves colitis and response to corticosteroids by attenuating virulence of Crohn’s disease–associated bacteria
- Adjunctive Corticosteroids in Pediatric Meningitis: Current Evidence, Clinical Controversies, and Future Directions.
- Individual variation in glucocorticoid plasticity to temperature is not associated with reproductive success in a wild songbird population
- Genetic disruption of cutaneous de novo glucocorticoid synthesis: a CRISPR-Cas9 CYP11B1-knockout human epidermal model
- Neuroprotective potential of vitamin D3 against glucocorticoid-induced neurotoxicity: Focus on calcium-binding proteins and neuroinflammation in a rat model
BibTeX
@article{seong2026putative,
title = {{A putative pharmacodynamic ceiling for topical corticosteroids in atopic dermatitis: a steroid-primed inflammasome and caspase-1–mediated glucocorticoid receptor cleavage}},
author = {Seung-Yong Seong},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1988621},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1988621/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A putative pharmacodynamic ceiling for topical corticosteroids in atopic dermatitis: a steroid-primed inflammasome and caspase-1–mediated glucocorticoid receptor cleavage
AU - Seung-Yong Seong
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1988621
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1988621/full
AB - Background: Topical corticosteroids (TCS) remain the first-line anti-inflammatory treatment for mild-to-moderate atopic dermatitis (AD), yet continuous use is constrained by cutaneous toxicity, rebound phenomena and topical steroid withdrawal (TSW). Objective: This article proposes a mechanistic model in which glucocorticoids prime a cutaneous inflammasome axis that both sustains relapse risk and progressively reduces glucocorticoid receptor (GR) availability through caspase-1-mediated cleavage. Methods: A narrative, hypothesis-generating synthesis integrated clinical trials of proactive maintenance and non-steroidal topicals with mechanistic data on glucocorticoid signaling, NLRP3 inflammasome biology, purinergic P2X7 receptor (P2X7R) pathways, keratinocyte-immune crosstalk and GR regulation. Hypothesis: TCS are among the most effective topical agents for AD, but prolonged use is associated with steroid-associated rosacea-like dermatitis and TSW, iatrogenic phenotypes with no non-steroidal counterpart. Residual relapse under proactive maintenance is of comparable magnitude whether maintenance is steroidal or non-steroidal and is therefore taken here as the clinical problem to be solved. Glucocorticoids can transactivate NLRP3 in myeloid cells and induce CCL20 and TLR2 in keratinocytes, increasing inflammasome sensor abundance and sensitivity. On tapering or withdrawal, under continued subclinical type 2 inflammation, barrier disruption, microbial colonization and LL-37 and ATP release, the primed P2X7R-NLRP3 axis may discharge. In leukemia cells, active caspase-1 cleaves GR, reducing receptor occupancy at glucocorticoid-responsive elements and conferring steroid resistance; analogous activity in skin would be expected to narrow progressively the GR pool available to subsequent TCS doses. Conclusions: The model reframes steroid-associated rosacea-like dermatitis and TSW as predictable discharges of a pharmacologically primed inflammasome rather than as idiosyncratic toxicity, with the limit on prolonged TCS use proposed to be set by P2X7R-NLRP3-caspase-1-GR interactions. It favors an add-on strategy co-administered with TCS from induction onward, targeting inflammasome assembly or caspase-1 activity to preserve GR integrity and prolong safe first-line steroid use, rather than relying on second-line non-steroidal substitution alone. No new experiments, patient-level analyses or meta-analyses are presented; prospective studies should quantify inflammasome activation, extracellular ATP and GR cleavage in human skin across the induction, maintenance, tapering and withdrawal phases of TCS therapy.
SN - 1664-3224
ER -