Abstract
BackgroundInterleukin-1β (IL-1β) is important for host resistance against Mycobacterium tuberculosis (Mtb) infections. The response of the dendritic cell inflammasome during Mtb infections has not been investigated in detail.Methodology/Principal FindingsHere we show that Mtb infection of bone marrow-derived dendritic cells (BMDCs) induces IL-1β secretion and that this induction is dependent upon the presence of functional ASC and NLRP3 but not NLRC4 or NOD2. The analysis of cell death induction in BMDCs derived from these knock-out mice revealed the important induction of host cell apoptosis but not necrosis, pyroptosis or pyronecrosis. Furthermore, NLRP3 inflammasome activation and apoptosis induction were both reduced in BMDCs infected with the esxA deletion mutant of Mtb demonstrating the importance of a functional ESX-1 secretion system. Surprisingly, caspase-1/11-deficient BMDCs still secreted residual levels of IL-1βand IL-18 upon Mtb infection which was abolished in cells infected with the esxA Mtb mutant.ConclusionAltogether we demonstrate the partially caspase-1/11-independent, but NLRP3- and ASC- dependent IL-1β secretion in Mtb-infected BMDCs. These findings point towards a potential role of DCs in the host innate immune response to mycobacterial infections via their capacity to induce IL-1β and IL-18 secretion.
Highlights
The inflammasome is a multiprotein complex that initiates the maturation of pro-IL-1b and pro-IL-18 to their secreted products via the activation of caspase-1
These findings point towards a potential role of Dendritic cells (DCs) in the host innate immune response to mycobacterial infections via their capacity to induce IL-1b and IL-18 secretion
We demonstrate that bone marrow-derived dendritic cells (BMDCs) depend on ASC and NLRP3 but not NLRC4 or NOD2 for IL-1b secretion, which is similar to the inflammasome requirements in macrophages
Summary
The inflammasome is a multiprotein complex that initiates the maturation of pro-IL-1b and pro-IL-18 to their secreted products via the activation of caspase-1. The inflammasome consists frequently of three principle components: a NOD-like Receptor (NLR) that is a pattern recognition receptor (PRR), the adaptor protein ASC (apoptotic speck-containing protein with a CARD) and the inactive pro-caspase-1 protein [1,2]. Inflammasome activation leads to cytokine secretion but may cause pyroptosis, a specific form of cell death, that combines characteristics of necrotic and apoptotic death pathways [4,5]. The cleavage of chromosomal DNA is associated with pyroptosis but is not mediated via caspase activated DNase activation and does not produce the characteristic DNA fragmentation pattern associated with apoptotic cell death [6,10]. The response of the dendritic cell inflammasome during Mtb infections has not been investigated in detail
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