Langerhans Cell Modulation in Atopic Dermatitis Is TLR2/SOCS1-Dependent and JAK Inhibitor-Sensitive

Langerhans cells (LC) are epidermal dendritic cells building the skin's outermost immunological barrier and bridging innate and adaptive immune responses. Their sensing property of the microbiome via Toll-like receptors (TLR) is impaired in atopic dermatitis (AD). We hypothesize a desensitization of LC because of persistent Staphylococcus aureus exposure in AD and underlying mechanisms being TLR2-related.

Human LC generated from hematopoetic stem cells were desensitized via repetitive exposure to TLR2-ligands (priming) and compared to unprimed cells for their TLR-responsiveness. JAK inhibitors impact was evaluated. Maturation marker, migration marker and behavior, cytokine release, and downstream molecule regulation were addressed by flow cytometry, qPCR, and transwell and multiplex assays.

Primed LC mimicked the LC behavior in AD skin, exhibiting desensitization toward TLR2-mediated activation monitored by impaired CD83/CD80/CD86 and MHCII expression as well as impaired regulation of chemokines CCR6 and CCR7, migration competence, and Th17-driving cytokines. IL-18 and IL-1β were elevated under these conditions. Negative regulators of the TLR2 pathway, specifically SOCS1 and IRAKM, were significantly upregulated, whereas activating molecules were hardly affected. JAK inhibitors reduced SOCS1 expression in primed cells and restored activation markers CD83/80/86 and MHCII upon TLR2 engagement, but had no effect on IRAKM expression.

Primed LC mimic the impaired LC-responsiveness toward TLR2 in AD skin. Our findings unravel a new direct contribution of LC to AD-associated IL-1β and IL-18 under these conditions and shed light on the mechanistical role of SOCS1 and the mode of action of JAK inhibitors.