AUTHOR=Ben Abdallah Hakim , Bregnhøj Anne , Ghatnekar Gautam , Iversen Lars , Johansen Claus 

TITLE=Heat shock protein 90 inhibition attenuates inflammation in models of atopic dermatitis: a novel mechanism of action

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1289788

DOI=10.3389/fimmu.2023.1289788

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD).</p></sec><sec><title>Objectives</title><p>Our study aimed to investigate HSP90 as a novel target to treat AD.</p></sec><sec><title>Methods</title><p>Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNγ or TNF/IL-4) and a mouse model established by MC903 applications.</p></sec><sec><title>Results</title><p>In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1- (<italic>TNF</italic>, <italic>IL1B</italic>, <italic>IL6</italic>) and Th2-associated (<italic>CCL17</italic>, <italic>CCL22, TSLP)</italic> cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (<italic>Il1b, Il4, Il6, Il13</italic>), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model.</p></sec><sec><title>Conclusion</title><p>HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD.</p></sec>