Mitochondrial damage activates the NLRP10 inflammasome.

Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adapter ASC and caspase-1, inducing gasdermin D (GSDMD)-dependent cell death and maturation and release of IL-1ß and IL-18. The triggers and activation mechanisms of several inflammasome-forming sensors are not well understood. Here we show that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. While the AIM2 inflammasome can also sense mitochondrial demise by detecting mitochondrial DNA (mtDNA) in the cytosol, NLRP10 monitors mitochondrial integrity in an mtDNA-independent manner, suggesting the recognition of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, in which it can also assemble an inflammasome. Our study shows that this inflammasome surveils mitochondrial integrity. These findings might also lead to a better understanding of mitochondria-linked inflammatory diseases.

Inflammasome-induced extracellular vesicles harbour distinct RNA signatures and alter bystander macrophage responses.

Infectious organisms and damage of cells can activate inflammasomes, which mediate tissue inflammation and adaptive immunity. These mechanisms evolved to curb the spread of microbes and to induce repair of the damaged tissue. Chronic activation of inflammasomes, however, contributes to non-resolving inflammatory responses that lead to immuno-pathologies. Inflammasome-activated cells undergo an inflammatory cell death associated with the release of potent pro-inflammatory cytokines and poorly characterized extracellular vesicles (EVs). Since inflammasome-induced EVs could signal inflammasome pathway activation in patients with chronic inflammation and modulate bystander cell activation, we performed a systems analysis of the ribonucleic acid (RNA) content and function of two EV classes. We show that EVs released from inflammasome-activated macrophages carry a specific RNA signature and contain interferon ß (IFNß). EV-associated IFNß induces an interferon signature in bystander cells and results in dampening of NLRP3 inflammasome responses. EVs could, therefore, serve as biomarkers for inflammasome activation and act to prevent systemic hyper-inflammatory states by restricting NLRP3 activation in bystander cells.

CCL17-expressing dendritic cells in the intestine are preferentially infected by Salmonella but CCL17 plays a redundant role in systemic dissemination.

INTRODUCTION: Salmonella spp. are a recognized and global cause of serious health issues from gastroenteritis to invasive disease. The mouse model of human typhoid fever, which uses Salmonella enterica serovar Typhimurium (STM) in susceptible mouse strains, has revealed that the bacteria gain access to extraintestinal tissues from the gastrointestinal tract to cause severe systemic disease. Previous analysis of the immune responses against Salmonella spp. revealed the crucial role played by dendritic cells (DCs) in carrying STM from the intestinal mucosa to the mesenteric lymph nodes (mLNs), a key site for antigen presentation and T cell activation. In this study, we investigated the influence of chemokine CCL17 on the dissemination of STM. METHODS: WT, CCL17/EGFP reporter, or CCL17-deficient mice were infected orally with STM (SL1344) or mCherry-expressing STM for 1-3 days. Colocalization of STM with CCL17-expressing DCs in Peyer's patches (PP) and mLN was analyzed by fluorescence microscopy. In addition, DCs and myeloid cell populations from naïve and Salmonella-infected mice were analyzed by flow cytometry. Bacterial load was determined in PP, mLN, spleen, and liver 1 and 3 days after infection. RESULTS: Histological analysis revealed that CCL17-expressing cells are located in close proximity to STM in the dome area of PP. We show that, in mLN, STM were preferentially located within CCL17+ rather than CCL17- DCs, besides other mononuclear phagocytes, and identified the CD103+ CD11b- DC subset as the main STM-carrying DC population in the intestine. STM infection triggered upregulation of CCL17 expression in specific intestinal DC subsets in a tissue-specific manner. The dissemination of STM from the gut to the mLN, however, was only moderately influenced by the presence of CCL17. CONCLUSION: CCL17-expressing DCs were preferentially infected by Salmonella in the intestine in comparison to other DC. Nevertheless, the production of CCL17 was not essential for the early dissemination of Salmonella from the gut to systemic organs.