Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent

Abstract

Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent,Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1β(IL-1β), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanism—priming and licensing of inflammasome activation—but there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate ifN. meningitidisactivates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected toN. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup CN. meningitidis(FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereaslpxAwas unable to induce caspase-1 activity as well as to induce IL-1βrelease. While thelpxAmutant induced a priming response, measured as increased expression ofNLRP3andIL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components ofN. meningitidiscontribute to the priming of the inflammasome activity, LOSper seis to be considered as the central component ofN. meningitidisvirulence, responsible for both priming and licensing of inflammasome activation.