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AMPK activation modulates IL-36-induced inflammatory responses by regulating IκBζ expression in the skin.

Authors :
Huang YT
Chiu LY
Lu PH
Hsiao PF
Wang JY
Lu PH
Wu NL
Source :
British journal of pharmacology [Br J Pharmacol] 2024 Aug; Vol. 181 (15), pp. 2429-2442. Date of Electronic Publication: 2024 Mar 26.
Publication Year :
2024

Abstract

Background and Purpose: The interleukin (IL)-36 pathway is a critical player in the pathogenesis of pustular psoriasis. However, therapies targeting this pathway are limited or unaffordable (e.g. the anti-IL-36 receptor antibody). AMP-activated protein kinase (AMPK), a regulator of cellular energy and metabolism, is known to participate in inflammatory diseases. However, its role in IL-36-induced skin inflammation remains unclear. Therefore, we sought to investigate the role of AMPK signals in regulating IL-36-induced responses in the skin.<br />Experimental Approach: IL-36-stimulated primary normal human epidermal keratinocytes (NHEKs) and IL-36-injected (intradermally) BALB/c mice served as the cell and animal models, respectively. Additionally, 5-aminoimidazole-4-carboxamide riboside (AICAR) and A769662 served as AMPK activators.<br />Key Results: AICAR and A769662 significantly suppressed the IL-36-induced IL-8 (CXCL8) and CCL20 production from NHEKs. IL-36-induced IκBζ protein expression was prominently reduced and IKK/IκBα phosphorylation was attenuated by AICAR and A769662. Conversely, AMPKα knockdown increased IκBζ protein expression and IKK/IκBα phosphorylation in IL-36-treated NHEKs. Furthermore, AICAR and A769662 enhanced IL-36-induced-IκBζ protein degradation via the proteasome-dependent but not the lysosome-dependent pathway. Pretreatment of NHEKs with IL-36 slightly suppressed the AICAR- and A769662-triggered phosphorylation of AMPK and acetyl-CoA carboxylase. In the mouse model, topical application of AICAR significantly reduced ear swelling, redness, epidermal thickening, neutrophil infiltration and inflammatory and antimicrobial peptide gene expression.<br />Conclusion and Implications: AMPK activation suppresses IL-36-induced IL-8 and CCL20 release by regulating IκBζ expression in keratinocytes and reduces IL-36-induced skin inflammation in mice, suggesting that AMPK activation is a potential strategy for treating patients with IL-36-mediated inflammatory skin disorders.<br /> (© 2024 British Pharmacological Society.)

Details

Language :
English
ISSN :
1476-5381
Volume :
181
Issue :
15
Database :
MEDLINE
Journal :
British journal of pharmacology
Publication Type :
Academic Journal
Accession number :
38532634
Full Text :
https://doi.org/10.1111/bph.16354