Journal Article

Cutaneous inflammasome driving ASC / gasdermin-D activation and IL-1β-secreting macrophages in severe atopic dermatitis

Orfali, Raquel Leão, da Silva, Luiz Fernando Ferraz, Pereira, Naiura Vieira, Kawakami, Joyce Tiyeko, Sato, Maria Notomi, Ramos, Yasmim Álefe Leuzzi, Sotto, Mírian Nacagami, Aoki, Valeria

2024

Overview

Atopic dermatitis (AD) is an inflammatory skin disease with intense pruritus, and chronic skin colonization by Staphylococcus aureus . To understand the inflammatory status in AD, we investigated the inflammasome complex, that activates ASC (Apoptosis-associated speck-like protein containing a CARD), caspase-1 and GSDMD (gasdermin-D), and production of IL-1β and IL-18. We aimed to evaluate the expression of the inflammasome pathway in the skin of adults with AD. Thirty patients with moderate to severe AD and 20 healthy controls were enrolled in the study. We performed the analysis of the inflammasome components NLRP1, NLRP3, AIM-2, IL-1β, IL-18, Caspase-1, ASC, GSDMD, and CD68 expression (macrophage marker) by immunohistochemistry and immunofluorescence. The main findings included increased expression of NLRP3, NLRP1 and AIM-2 at dermal level of severe AD; augmented IL-18 and IL-1β expression at epidermis of moderate and severe patients, and in the dermis of severe AD; augmented expression of ASC, caspase-1 and GSDMD in both epidermis and dermis of moderate and severe AD. We detected positive correlation between caspase-1, GSDMD and IL-1β (epidermis) and caspase-1 (dermis) and AD severity; NLRP3, AIM-2 and IL-1β, and NLRP3 with IL-18 in the epidermis; ASC, GSDMD and IL-1β, and NLRP3, AIM-2, caspase-1, and IL-18 in the dermis. We also evidenced the presence of CD68 + macrophages secreting GSDMD, ASC and IL-1β in moderate and severe AD. Cutaneous macrophages, early detected in moderate AD, have its role in the disease inflammatory mechanisms. Our study indicates a canonical activation pathway of inflammasomes, reinforced by the chronic status of inflammation in AD. The analysis of the inflammasome complex evidenced an imbalance in its regulation, with increased expression of the evaluated components, which is remarkably in severe AD, emphasizing its relevance as potential disease biomarkers and targets for immunomodulatory interventions.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Adult / Antigens, CD - metabolism / Antigens, Differentiation, Myelomonocytic - metabolism / Apoptosis / Apoptosis Regulatory Proteins - metabolism / Atopic dermatitis / CARD Signaling Adaptor Proteins - metabolism / Case-Control Studies / Caspase 1 - metabolism / Caspase-1 / CD68 Molecule / Cell activation / Cell death / Cytokines / Dermatitis / Dermatitis, Atopic - immunology / Dermatitis, Atopic - metabolism / Dermatitis, Atopic - pathology / Dermatology / Dermis / DNA-Binding Proteins / Epidermis / Epidermis - immunology / Epidermis - metabolism / Epidermis - pathology / Female / Gasdermins / Gene expression / Humans / IL-1β / Immunofluorescence / Immunohistochemistry / Immunomodulation / Inflammasomes / Inflammasomes - immunology / Inflammasomes - metabolism / Interleukin 18 / Interleukin-18 - metabolism / Interleukin-1beta - metabolism / Intracellular Signaling Peptides and Proteins - metabolism / Macrophages / Macrophages - immunology / Macrophages - metabolism / Male / Medicine / Medicine & Public Health / Middle Aged / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / NLR Proteins - metabolism / Phosphate-Binding Proteins - metabolism / Pruritus / Research Letter / Severity of Illness Index / Skin - immunology / Skin - metabolism / Skin - pathology / Skin diseases / Young Adult