The Effect of Mevalonate, Zoledronate, and BCG Induction on the Monocyte/Macrophage Phenotype

Abstract

Innate immune cells, mainly monocytes/macrophages, upon their first encounter with a pathogen, form long-term nonspecific immunological memory, so-called “trained immunity.” In its formation, an important role is played by metabolites of the mevalonate pathway. The purpose of the study was to investigate the effect of mevalonate pathway modulators, mevalonate and zoledronate, on the formation of trained immunity in human and animal monocytes/macrophages. Human monocyte-like cells THP-1 and U-937 and peritoneal macrophages from BALB/c mice were used. Trained immunity was induced in vitro by incubating THP-1 and U-937 cells with inactivated mycobacteria of the bacillus Calmette–Guérin (BCG) vaccine strain for 24 and 72 h and in vivo by intraperitoneal injection of BCG to BALB/c mice and isolation of peritoneal macrophages on the seventh day after infection (lag phase). Cell hyperreactivity was assessed by the response to a second stimulus with bacterial lipopolysaccharide (LPS) and mevalanate or zoledranate in the presence or absence of LPS. The level of lactate, cytokines (IL-1β, TNF-α, IL-10), nitric oxide and glucose was evaluated in conditioned media from cells. It was found that monocyte-like THP-1 and U-937 cells respond differently as concerns the production of cytokines and lactate and the consumption of glucose to the BCG stimulus with or without the lag phase. Mevalonate and zoledronate alone or in combination with LPS also differentially stimulate cytokine secretion. The presence of the lag phase for human monocyte-like cells is essential for the level of cytokine production and glucose consumption. Peritoneal macrophages have been shown to increase the release of proinflammatory cytokines in response to LPS, mevalonate, and zoledronate. Mevalonate and zoledronate induce trained immunity in monocytes/macrophages.