Memantine Displays Antimicrobial Activity by Enhancing Escherichia coli Pathogen-Induced Formation of Neutrophil Extracellular Traps

Abstract

Bacterial infection remains one of the leading causes of death worldwide due to the continuous rise of multiple antibiotic-resistant bacteria. Focusing solely on bacteria as the drug targets is a major limitation inherent in the conventional antibiotic therapy. Recently, host-directed therapies have become such an innovative approach to modulate the host defense system and the interplay of innate and adaptive immunity. Our previous studies showed that memantine (MEM), an α7 nAChR antagonist, could efficiently block multi-drug resistant Escherichia coli-caused bacteremia and meningitis in a mouse model. However, the underlying mechanisms that govern the antibacterial effects of MEM are still unknown. In this study, we demonstrated that MEM is able to significantly suppress E. coli infection by enhancing E. coli-induced formation and release of NETs in vitro and in vivo. MEM could promote the trapping and bactericidal activities of the polymorphonuclear neutrophils (PMNs) in a manner dependent on α7 nAChR, since knockdown of this receptor noticeably reduces the survival ability of bacteria in PMNs while MEM no longer affects the survival of bacteria in PMNs. Our results also showed that when the expression of S100A9, an antiseptic protein, is inhibited, pathogen survival rates in PMNs increase significantly. MEM reverses this effect in a concentration-dependent manner. MEM stimulates the production of MPO, S100A9, and DNA in PMNs and accelerates the release of depolymerized chromatin fibers into the extracellular space, suggesting the formation of NETs. Taken together, our data suggest that MEM effectively blocks bacterial infection through the promotion of the antibacterial function of NETs induced by E. coli.

Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis

“…A microarray analysis indicated the suppression of neutrophil immune and inflammatory function in patients with sepsis 24 h after admission [ 12 ]. Neutrophils may also have reduced antimicrobial function and impaired ability to inhibit adaptive immunity in vitro [ 13 ]. Hence, it is necessary to clarify the roles of neutrophils in dysregulated immune response that leads to deleterious outcomes in patients with sepsis.…”

Methylprednisolone Induces Extracellular Trap Formation and Enhances Bactericidal Effect of Canine Neutrophils

“…The fact that E. coli as a Gram negative bacteria has lipopolysaccharides in the outer membrane which induces NET release can also result in the high amount of free DNA [ 19 ] to the suspected inductive property of methylprednisolone. A NET induction of E. coli was shown by immunofluorescence microscopy [ 74 , 75 ]. However, this NET release is not automatically associated with lower survival factors because E. coli is mainly killed intracellularly [ 76 ].…”

Phagocytosis, Degranulation and Extracellular Traps Release by Neutrophils—The Current Knowledge, Pharmacological Modulation and Future Prospects

“…Memantine is a drug approved for Alzheimer’s disease and tested for other applications ( Lu and Nasrallah, 2018 ). It was shown that through stimulation of MPO production, it increases NET formation ( Peng et al, 2020 ). Clozapine, the first atypical antipsychotic drug, whose side effects involve agranulocytosis ( Khokhar et al, 2018 ) was also tested and was shown to exert no influence on NET formation ( Irizarry-Caro et al, 2018 ).…”