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The contact allergen NiSO4 triggers a distinct molecular response in primary human dendritic cells compared to bacterial LPS

ABSTRACT: Allergic contact dermatitis (ACD) is the most prevalent form of immunotoxicity in humans. Dendritic cells (DC) play a central role in the pathogenesis of ACD, particularly during the sensitization phase to a specific allergen. Upon activation, DCs maturate and migrate to draining lymph nodes which is accompanied by major metabolic and phenotypic alterations that facilitate the presentation of the captured antigen to prime naïve T cells. Nevertheless, knowledge on the molecular effects during maturation of DCs in the context of ACD remain scarce. Here, we present a global proteomic analysis of monocyte-derived dendritic cells (MoDC) treated with NiSO4, the most prominent cause of ACD. Proteomic alterations induced after treatment with NiSO4 were compared to the bacterial trigger lipopolysaccharide (LPS). Both substances possess a similar TLR4 binding capacity, which may help to identify allergy-specific effects compared to bacterial activation. MoDCs treated for 24 h with 2.5 µg/ ml LPS displayed a very strong immunological response, characterized by upregulation of DC activation markers, secretion of proinflammatory cytokines and stimulation of T cell proliferation. Similar immunological responses were observed after treatment with 400 µM NiSO4 but less pronounced. Both triggered TLR4 and TREM1 pathways. However, NiSO4 in addition, also activated hypoxic and apoptotic pathways, which might have overshadowed initial signaling. Moreover, our proteomic data support the importance of Nrf2 as a key player in mediating sensitization since many Nrf2 targets genes were strongly upregulated on protein level selectively after treatment with NiSO4. Strikingly, NiSO4 stimulation induced cellular hypocholesterolemia which was counteracted by the induction of genes and proteins relevant for cholesterol biosynthesis. Our proteomic study allowed for the first time to better characterize some of the fundamental differences between NiSO4 and LPS-triggered activation of MoDCs, providing an important contribution to the molecular understanding of contact allergy.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Dendritic Cell, Blood

DISEASE(S): Nickel Allergic Contact Dermatitis

SUBMITTER: Kristin Schubert

LAB HEAD: Kristin Schubert

PROVIDER: PXD022599 | Pride | 2021-03-29

REPOSITORIES: Pride

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The contact allergen NiSO4 triggers a distinct molecular response in primary human dendritic cells compared to bacterial LPS

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