The memory immunity response via long-term metabolic and epigenetic reprogramming in innate immune cells has been termed “trained immunity”1, 2, 3, which can be triggered by β-glucan(4), BCG(5), and oxidized low-density lipoprotein(6) accompanying long-term functional reprogramming events such as increased host defense against unrelated infections7, 8. Trained immunity plays a double-edged role, where moderate activation of trained immunity is beneficial to the clearance of bacterial infection, but excessive activation could conversely lead to the development of disease, including autoimmune disorders and cardiovascular diseases9, 10. Evidence indicates that urate triggers epigenetic changes, resulting in an altered functional state that manifests as long-term systemic inflammation observed in gout11, 12. The amount of pro-inflammatory cytokines produced by PBMCs after re-stimulation was higher in hyperuricaemic individuals than in controls(13). Allergen-triggered inflammation drives an inflammatory transcriptional reprogramming and may exacerbate chronic type 2 airway inflammation, which is reliant on TNF(14). OxLDL induced trained immunity accompanied by low-grade inflammation, which may contribute to atherosclerosis development(6). This evidence suggests the inhibition of the maladaptive activation of trained immunity may be effective strategies for disease development.

Inhibition of mTOR, HIF-1α, and Akt resulted in a dose-dependent inhibition of cytokines production in trained monocytes4, 15, suggesting the innate memory depended on Akt/mTOR/HIF-1α signaling pathway. Moreover, pieces of evidence suggest that interleukin-1 (IL-1) 1family cytokines play an essential role in regulating and initiating innate immune memory15, 16, 17. IL-37 and IL-38, the anti-inflammatory cytokines of the IL-1 family members, are promising targets for therapies as they can reduce the induction of trained immunity, both cytokines mainly act by inhibiting the activation of mTOR and preventing epigenetic changes18, 19, 20.

Clostridium perfringens (C. perfringens)2 is a zoonotic pathogen that causes gastroenteritis, gas gangrene, and necrotic enteritis derived from its different toxins21, 22. Additionally, food safety issues caused by C. perfringens are people’s concerns. Antibiotics can contribute to the development of resistant germs; thus, the study of the host-pathogen interaction is necessary. Innate immune memory leads to a range of subsequent cellular antimicrobial events; however, these effects may result in an excessive inflammatory reaction.

Dihydroartemisinin (DHA)3 is the active metabolite of artemisinin-like compounds in vivo(23) and has exhibited multiple biomedical activities including anti-inflammatory, anti-cancer, and immunoregulatory effects24, 25. In this study, we show that heat-killed Candida albicans (HKCA)4 priming enhanced innate responses against C. perfringens, and DHA blocks mTOR signaling and AIM2 inflammasome activation induced by HKCA, thus suppressing the production of cytokines, ETs release and autophagy proteins expression in response to C. perfringens. Given the novelty of its immunomodulatory potential, we suggest that DHA may be useful as a therapy in conditions characterized by excessively trained immunity such as autoinflammatory diseases.