Mykicki Nadine, Eble Johannes A, Weighardt Heike, Gonnelli Elena, Schneeweiß Maria, Esser Charlotte, Weishaupt Carsten, Rezaei Maryam, Förster Irmgard, Schwab Nicholas, Wiendl Heinz, Clausen Björn E, Meuth Sven G, Loser Karin
Department of Immunology, University of Oldenburg, Oldenburg 26129, Germany.
Institute for Physiological Chemistry and Biochemistry, University of Münster, Münster 48149, Germany.
Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2424009122. doi: 10.1073/pnas.2424009122. Epub 2025 Sep 2.
Environmental stimuli, including the exposure to ultraviolet (UV)-B light, are known to play a role in the modulation of immune-mediated mechanisms in multiple sclerosis (MS). In experimental autoimmune encephalomyelitis (EAE), we have shown that UV-B irradiation ameliorates disease outcome by regulatory T cells (Treg) expansion. Moreover, the UV-B-mediated induction of Treg numbers was also observed in MS. The aryl hydrocarbon receptor (AhR) can be activated by environmental factors including UV-B-induced photoproducts of tryptophan. Thus, we investigated the role of AhR during the transmission of UV-B irradiation. Therefore, wild-type (WT) and AhR-deficient mice (AhR) were irradiated with UV-B light and immunized with myelin oligodendrocyte glycoprotein (MOG)-peptide. In WT mice it was shown that UV-B irradiation reduces EAE symptoms by Treg expansion. This effect was abrogated in animals with AhR deficiency. To better understand the underlying mechanisms of AhR regulation, we used mice with a deletion of AhR specifically in different subsets of antigen-presenting cells (APC) that have been shown to mediate the expansion of Treg. Interestingly, we could show that the AhR activation in murine cutaneous APC was sufficient to switch APC from a stimulatory into a regulatory phenotype, and moreover, responsible for APC cell maturation and migration into regional lymph nodes. Thus, our data indicate that AhR activation in APC might be required for UV-B-mediated immunosuppression during MOG-induced EAE. Hence, activation of AHR in tissue-resident APC, potentially by low-dose UV-B irradiation, might be beneficial as an adjuvant treatment in inflammatory or degenerative diseases of the central nervous system.
已知包括暴露于紫外线B（UV-B）光在内的环境刺激在多发性硬化症（MS）免疫介导机制的调节中发挥作用。在实验性自身免疫性脑脊髓炎（EAE）中，我们已经表明UV-B照射通过调节性T细胞（Treg）扩增改善疾病结局。此外，在MS中也观察到UV-B介导的Treg数量诱导。芳烃受体（AhR）可被包括UV-B诱导的色氨酸光产物在内的环境因素激活。因此，我们研究了AhR在UV-B照射传递过程中的作用。因此，用UV-B光照射野生型（WT）和AhR缺陷小鼠（AhR），并用髓鞘少突胶质细胞糖蛋白（MOG）肽进行免疫。在WT小鼠中，已表明UV-B照射通过Treg扩增减轻EAE症状。在AhR缺陷的动物中这种效应被消除。为了更好地理解AhR调节的潜在机制，我们使用了在已被证明介导Treg扩增的不同抗原呈递细胞（APC）亚群中特异性缺失AhR的小鼠。有趣的是，我们可以表明鼠皮肤APC中的AhR激活足以使APC从刺激性表型转变为调节性表型，而且，负责APC细胞成熟和迁移到局部淋巴结。因此，我们的数据表明在MOG诱导的EAE期间，APC中的AhR激活可能是UV-B介导的免疫抑制所必需的。因此，潜在地通过低剂量UV-B照射激活组织驻留APC中的AHR，可能作为中枢神经系统炎症或退行性疾病的辅助治疗是有益的。
