Shigella meets dendritic cells: the kiss of death
The immune system responds to infection in a variety of ways, including activation of pathways that promote survival to eliciting programmed cell death. The initial response to infection is geared toward eradicatingor containingthe infection; this can be achieved byactivation of inflammatory pathway, recruitment of immune cells to the site of infection, production of antimicrobial peptides and cytokines. However, if the condition is unresolved, cell death signaling pathways are engaged to eliminate the infected cells from the organism. Notably, the possibility exists that these mechanisms are not mutually exclusive. This complexity of regulatory mechanisms is observed in the invasive process of Shigella spp., an enteric pathogen that causes bacillary dysentery in humans. In epithelial cells, Shigella triggers NF-kB via peptidoglycan (PGN) sensing by the PRR Nod1, thereby inducing the secretion of CXCL8. This pathogen is equally able to induce various types of cell death in different cell populations. Apoptosis, necrosis and pyroptosis constitute the principal mechanisms by which programmed host cell death occurs.
Here, we have investigated on the molecular mechanisms and cell effectors governing the balance between survival and cell death in bone marrow-derived dendritic cells (BMDCs) infected with Shigella. DC include a family of professional antigen presenting cells (APC), characterized by the unique ability to modulate T cell response. Our results definitely show that mouse DCs respond to Shigella infection by triggering two cell death pathways: i) a rapid and massive apoptosis via caspase-3 activation; ii) caspase-1–mediated pyroptosis and the ensuing IL-1band IL-18 release. The IL-1band IL-18 release by the infected immuno-competent cells, such as dendritic cells and macrophages, has been reported to relay on host inflammasome assembly and caspase-1 activation. For this purpose, we also characterize the inflammasome platforms involved in BMDCs pyroptosis. We demonstrate that MyD88–dependent signaling pathway plays a pivotal role in IL-1brelease, whereas is dispensable for IL-18. On the contrary, caspase-1 knock-out BMDCs infected with Shigella are strongly impaired in both IL-1band IL-18 release. Moreover, NLRC4 is not involved in cell death induction and inflammasome assembly in BMDCs infected with Shigella; however, we identified Naip5 as the main NLR-protein, able to induce caspase activation and IL-18 release, allowing BMDCs cell death.