Abstract
Accumulation of polymorphonuclear neutrophils (PMN) into the subarachnoidal space is one of the hallmarks of Neisseria meningitidis infection. In this study, we evaluated the ability of outer membrane vesicles (OMV) from N. meningitidis B to stimulate cytokine production by neutrophils. We found that PMN stimulated in vitro by OMV produce proinflammatory cytokines and chemokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta. A considerable induction of gamma interferon (IFN-gamma)-inducible protein 10 (IP-10) mRNA transcripts, as well as extracellular IP-10 release, was also observed when neutrophils were stimulated by OMV in combination with IFN-gamma. Furthermore, PMN stimulated by OMV in the presence of IFN-gamma demonstrated an enhanced capacity to release TNF-alpha, IL-1beta, IL-8, and MIP-1beta compared to stimulation with OMV alone. In line with its downregulatory effects on neutrophil-derived proinflammatory cytokines, IL-10 potently inhibited TNF-alpha, IL-1beta, IL-8, and MIP-1beta production triggered by OMV. Finally, a neutralizing anti-TNF-alpha monoclonal antibody (MAb) did not influence the release of IL-8 and MIP-1beta induced by OMV, therefore excluding a role for endogenous TNF-alpha in mediating the induction of chemokine release by OMV. In contrast, the ability of lipopolysaccharide from N. meningitidis B to induce the production of IL-8 and MIP-1beta was significantly inhibited by anti-TNF-alpha MAb. Our results establish that, in response to OMV, neutrophils produce a proinflammatory profile of cytokines and chemokines which may not only play a role in the pathogenesis of meningitis but may also contribute to the development of protective immunity to serogroup B meningococci.