Abstract
The isoquinoline alkaloid berberine possesses many pharmacological activities including antibacterial infection. Although the direct bactericidal effect of berberine has been documented, its influence on the antibacterial functions of macrophages is largely unknown. As inflammasome activation in macrophages is important for the defense against bacterial infection, we aimed to investigate the influence of berberine on inflammasome activation in murine macrophages. Our results showed that berberine significantly increased ATP-induced inflammasome activation as reflected by enhanced pyroptosis as well as increased release of caspase-1p10 and mature interleukin-1β (IL-1β) in macrophages. Such effects of berberine could be suppressed by AMP-activated protein kinase (AMPK) inhibitor compound C or by knockdown of AMPKα expression, indicating the involvement of AMPK signaling in this process. In line with increased IL-1β release, the ability of macrophages to kill engulfed bacteria was also intensified by berberine. This was corroborated by the in vivo finding that the peritoneal live bacterial load was decreased by berberine treatment. Moreover, berberine administration significantly improved survival of bacterial infected mice, concomitant with increased IL-1β levels and elevated neutrophil recruitment in the peritoneal cavity. Collectively, these data suggested that berberine could enhance bacterial killing by augmenting inflammasome activation in macrophages through AMPK signaling.
Highlights
Berberine is an isoquinoline alkaloid present in many medicinal herbs including Rhizoma coptidis and Cortex phellodendri as their major active ingredient [1]
In view of the pivotal role of adenosine triphosphate (ATP)-induced inflammasome activation in the defense against bacterial infection and our preliminary data showing that berberine increased cell death in macrophages upon ATP treatment, we aimed to explore the effects of berberine on NLRP3 inflammasome activation in murine macrophages in response to ATP stimulation
This was corroborated by increased release of high mobility group box 1 (HMGB1) into the culture supernatants accompanied by a decrease of HMGB1 levels in the cell lysates (Figure 1C)
Summary
Berberine is an isoquinoline alkaloid present in many medicinal herbs including Rhizoma coptidis and Cortex phellodendri as their major active ingredient [1]. Several reports have showed that its anti-gastroenteritic and anti-dysenteric effects are largely attributed to its direct antimicrobial effect on bacterial pathogens [3,4,5,6,7] It is unknown whether berberine has potentiated the bacterial killing ability of the host’s phagocytes including macrophages. As a major consequence of inflammasome activation, the macrophages undergo pyroptosis while releasing inflammatory cytokines and danger signals, including interleukin-1β (IL-1β) and high mobility group box 1 (HMGB1). These molecules in turn recruit and activate other phagocytes such as neutrophils and monocytes [12], as well as enhancing their phagocytic and bacterial killing capacities [10]. Induction of inflammasome activation is a robust mechanism for macrophages to fight against bacterial infection
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