Norisoboldine restrains γδT17 cell activation and consequently alleviates psoriasis-like dermatitis in mice by selectively down-regulating glutaminolysis to decrease the level of α-ketoglutarate.

INTRODUCTION

Psoriasis, an inflammatory skin disease characterized by aberrant type 17 immunity, is effectively treated with monoclonal antibodies targeting IL-17, though with notable side effects. Given that γδT17 cells represent the primary sources of IL-17 in the dermis of psoriasis patients, targeting these cells to inhibit IL-17 expression constitutes a potential therapeutic strategy for psoriasis.

OBJECTIVE

To examine the effects and mechanisms of Norisoboldine (NOR) on γδT17 cell activation in psoriasis-like dermatitis mice.

METHODS

Imiquimod was used to induce mouse psoriasis-like dermatitis model, and bioinformatics analysis and multiple molecular biological methods were employed to evaluate the proportion of γδT17 cells and signals activation.

RESULTS

NOR alleviates imiquimod-induced psoriasis-like dermatitis in mice by restraining γδT17 cell activation. In γδT17 cells, NOR selectively down-regulated glutaminolysis and overexpression of glutaminolysis rate-limiting enzyme glutaminase 1 (GLS1) dampened the attenuation of NOR against γδT17 cell activation. Exogenous addition of glutamine and combination with GLS1 inhibitor BPTES significantly repressed and promoted γδT17 cell activation, respectively. Through exogenous supplementation of glutamate and its downstream metabolites, including fumaric acid, succinic acid, and isocitric acid, along with the interference of glutamate dehydrogenase and isocitrate dehydrogenase 1/2, we found that NOR selectively decreased the level of α-ketoglutarate (α-KG) to suppress γδT17 cell activation. The decrease of α-KG level led to downregulation of lysine-specific histone demethylase 6B expression, which in turn restrained demethylation of histone H3K27 in RORγt promoter, ultimately restraining γδT17 cell activation.

CONCLUSION

NOR can limit γδT17 cell activation to alleviate psoriasis-like dermatitis in mice by suppressing glutaminolysis, down-regulating the levels of α-KG, inhibiting the expression of KDM6b, and consequently increasing the trimethylation level of histone H3K27 in RORγt promoter. These findings attest to the beneficial effect of NOR in inhibiting γδT17 cell activation and offer a potential therapeutic approach for psoriasis.