Skin Colonization with S. aureus Can Lead to Increased NLRP1 Inflammasome Activation in Patients with Atopic Dermatitis

• Published in: Journal of investigative dermatology Vol. 143; no. 7; pp. 1268 - 1278.e8
• Main Authors: Vaher, Helen, Kingo, Kristiina, Kolberg, Peep, Pook, Martin, Raam, Liisi, Laanesoo, Anet, Remm, Anu, Tenson, Tanel, Alasoo, Kaur, Mrowietz, Ulrich, Weidinger, Stephan, Kingo, Külli, Rebane, Ana
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2023
• Subjects: Cytokines - metabolism; Dermatitis, Atopic - genetics; Dermatitis, Atopic - metabolism; Humans; Inflammasomes - metabolism; Interleukin-18 - genetics; Methicillin-Resistant Staphylococcus aureus; NLR Proteins; RNA, Messenger; Staphylococcus aureus - metabolism; KC; siRNA; AD; PS; eQTL; Th
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2023.01.013

The role of NLRP1 inflammasome activation and subsequent production of IL-1 family cytokines in the development of atopic dermatitis (AD) is not clearly understood. Staphylococcus aureus is known to be associated with increased mRNA levels of IL1 family cytokines in the skin and more severe AD. In this study, the altered expression of IL-1 family cytokines and inflammasome-related genes was confirmed, and a positive relationship between mRNA levels of inflammasome sensor NLRP1 and IL1B or IL18 was determined. Enhanced expression of the NLRP1 and PYCARD proteins and increased caspase-1 activity were detected in the skin of patients with AD. The genetic association of IL18R1 and IL18RAP with AD was confirmed, and the involvement of various immune cell types was predicted using published GWAS and expression quantitative trait loci datasets. In keratinocytes, the inoculation with S. aureus led to the increased secretion of IL-1β and IL-18, whereas small interfering RNA silencing of NLRP1 inhibited the production of these cytokines. Our results suggest that skin colonization with S. aureus may cause the activation of the NLRP1 inflammasome in keratinocytes, which leads to the secretion of IL-1β and IL-18 and thereby may contribute to the pathogenesis of AD, particularly in the presence of genetic variations in the IL-18 pathway.