Selective AhR knockout in langerin-expressing cells abates Langerhans cells and polarizes Th2/Tr1 in epicutaneous protein sensitization

Abstract

The aryl hydrocarbon receptor (AhR) represents an environmental sensor regulating immune responses. In the skin, AhR is expressed in several cell types, including keratinocytes, epidermal Langerhans cells (LC), and dermal dendritic cells (DC). The mechanisms how AhR activates or inhibits cutaneous immune responses remain controversial, owing to differences in the cell-specific functions of AhR and the different activating ligands. Therefore, we sought to investigate the role of AhR in LC and langerin+and negative DC in the skin. To this aim, we generated Langerin-specific and CD11c-specific knockout (−/−) mice lacking AhR, respectively, in LC and Langerin+dermal DC and in all CD11c+cells. These were then tested in an epicutaneous protein (ovalbumin, Ova) sensitization model. Immunofluorescence microscopy and flow cytometry revealed that Langerin-AhR−/−but not CD11c-AhR−/−mice harbored a decreased number of LC with fewer and stunted dendrites in the epidermis as well as a decreased number of LC in skin-draining lymph nodes (LN). Moreover, in the absence of AhR, we detected an enhanced T helper type-2 (Th2) [increased interleukin 5 (IL-5) and interleukin 13 (IL-13)] and T regulatory type-1 (Tr1) (IL-10) response when LN cells were challenged with Ova in vitro, though the number of regulatory T cells (Treg) in the LN remained comparable. Langerin-AhR−/−mice also exhibited increased blood levels of Ova-specific immunoglobulin E (IgE). In conclusion, deletion of AhR in langerin-expressing cells diminishes the number and activation of LC, while enhancing Th2 and Tr1 responses upon epicutaneous protein sensitization.

Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor

“…Previous studies suggest that repair of the EPB is not dependent on AHR derived from Langerhans cells (Haas et al, 2016). However, during epicutaneous sensitization, Langerhans-specific loss of AHR led to decreased Langerhans cells number and function and ll Article dysregulated T cell responses (Hong et al, 2020). Thus, AHR likely represents a sensor for Langerhans cell activation as part of the immunological barrier.…”

Aryl hydrocarbon receptor/nuclear factor E2‐related factor 2 (AHR/NRF2) signalling: A novel therapeutic target for atopic dermatitis

“…62 AHR knockout in langerin expressing cells led to decreased Langerhans cell activation and quantity while enhancing Th2 and T regulatory type 1 cells. 63 AHR activation promotes differentiation of monocytes into dendritic cells while decreasing differentiation into macrophages. 64 Asthma, a closely related atopic disease to AD, was shown to be attenuated by AHR activation via polarization macrophages to an M2 anti-inflammatory phenotype in a mouse model.…”

“…AHR activation also downregulates expression of the high‐affinity receptor for IgE in Langerhans cells, which may dampen allergen‐induced inflammation in AD 62 . AHR knockout in langerin expressing cells led to decreased Langerhans cell activation and quantity while enhancing Th2 and T regulatory type 1 cells 63 . AHR activation promotes differentiation of monocytes into dendritic cells while decreasing differentiation into macrophages 64 .…”

Commensal Microbiota Regulates Skin Barrier Function And Repair Via Signaling Through The Aryl Hydrocarbon Receptor

“…Previous studies suggest that repair of the EPB is not dependent on AHR derived from Langerhans cells [58]. However, during epicutaneous sensitization, Langerhans specific loss of AHR led to decreased Langerhans cells number and function and dysregulated T cell responses [68]. Thus, AHR likely represents a sensor for Langerhans cell activation as part of the immunological barrier.…”