Project Details
Projekt
AHR as a master regulator in cutaneous and systemic autoimmunity
Applicant
Professorin Dr. Karin Loser
Subject Area
Dermatology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting many organs including the skin, the joints, the central nervous system or the kidneys. Although the pathophysiology of SLE is not completely understood yet, it has been shown that the interaction of impaired apoptotic clearance, up-regulated innate and adaptive immune responses, complement activation, autoantibodies, and imbalanced production of pro-inflammatory cytokines including type-1 interferons leads to the loss of self-tolerance. The onset of SLE requires a combination of genetic predisposition, environmental triggers, and immunological as well as hormonal factors. Among the environmental triggers of SLE, ultraviolet (UV) light is the most recognized one. UV irradiation contributes to the generation of tryptophan photoproducts, which act as endogenous ligands of the aryl hydrocarbon receptor (AHR), a transcription factor frequently suggested as sensor of external stimuli. Besides UV, dietary compounds or toxins, many of which are known as risk factors of SLE, represent AHR ligands and thus, activation of the transcription has been linked to autoimmune disorders. To investigate the role of AHR in systemic autoimmunity we generated a mouse model for SLE (K14-CD40L TG mice), which mimics typical characteristics of human disease including autoimmune dermatitis, nephritis, autoantibodies in the serum, and the presence of autoreactive T cells. Interestingly, AHR signaling was critical for disease development since K14-CD40L TG mice bred to an AHR-deficient background did not show any symptoms of SLE-like autoimmunity. Cell type-specific deletion of AHR revealed that AHR signaling in T cells seemed to be of minor relevance for the onset of CD40L-induced autoimmunity whereas mice deficient for AHR in Langerin+ dendritic cells (DC) were completely protected from disease, suggesting a central role of AHR in tissue-resident DC. Hence, we hypothesized that AHR might be critically involved in the development and progression of (systemic) autoimmune diseases by modulating the function of immune cells such as tissue-resident DC. Now we will try to better understand the ligand- and cell-specific character of AHR signaling during the onset of autoimmunity and three central questions shall be addressed: (1) Impact of AHR signaling on the development and progression of autoimmunity as well as functional relevance of the pathway in autoreactive cells; (2) Intervention in AHR signaling as potential therapeutic option for an (adjuvant) treatment of autoimmune diseases; (3) Relevance of the AHR pathway for the development of pathogenic or autoreactive human cells. Taken together, the project aims at better understanding AHR interactions in autoimmune processes, which might result in novel strategies to use this druggable ligand-activated transcription factor as a molecular target for the local or adjuvant treatment of autoimmune diseases.
DFG Programme
Research Units
