Characterization of type 2 interleukin-1 receptor (IL-1R2) as an inhibitory regulator of trained immunity in teleost.

Trained immunity refers to the immune memory of innate immune cells, which is driven by metabolic rewiring and epigenetic reprogramming after initial stimulation. Several endogenous inducers of trained immunity have been reported, such as oxidized low-density lipoprotein (oxLDL), interleukin, and interferon. However, the negative regulatory molecules of trained immunity remain largely elusive. In this study, we identify a member of IL-1 family receptors, interleukin-1 receptor 2 (IL-1R2), as a potential inhibitory regulator of trained immunity in turbot. Pre-incubating recombinant IL-1R2 protein (rIL-1R2) with turbot neutrophils could inhibit β-glucan-induced training phenotypes. Specifically, rIL-1R2 incubation significantly decreases the expression of genes involved in the TLR/IL-1R and downstream MAPK/NF-κB signaling pathway in trained neutrophils, and further reversing the elevated expression of pro-inflammatory cytokines such as IL-6 and TNF-α in response to bacterial reinfection. Moreover, rIL-1R2 inhibits the increasing production of intracellular reactive oxygen (ROS), myeloperoxidase (MPO) activity and neutrophil extracellular traps (NETs) in trained neutrophils, ultimately impairing the bacterial killing ability. Taken together, our work demonstrates that the decoy receptor IL-1R2 could negatively regulate trained immunity activation in turbot neutrophils. These findings enrich the theory of trained immunity in teleost fish and provide a potential target for disease prevention and treatment in aquaculture.