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Activation and Regulation of the NLRP3 Inflammasome

Final Report Summary - INFLAMMACT (Activation and Regulation of the NLRP3 Inflammasome)

The ERC InflammAct has revealed several novel mechanisms, by which the NLRP3 inflammasome is activated and regulated. For example, we have identified novel post-translational and posttranscriptional mechanisms of regulation of NLRP3 activation: We deciphered how a single phosphosite in the NLRP3 PYD domain licenses NLRP3 activity by regulating the interaction with the adapter molecule ASC. We have further characterized how alternative splicing of exon 5 in the NLRP3 LRR domain influences the activity of the protein products by regulating the binding of NEK7 to NLRP3. These data suggest that NLRP3 activation is under tight influence of multiple cellular signaling pathways that regulate direct posttranslational NLRP3 modification and we suggest that post-transcriptional mechanisms, i.e. alternative splicing, could regulate NLRP3 activity particularly in human immune cells.
We have furthermore demonstrated that NLRP3 can be activated by Western diet feeding of mice and that NLRP3 activation in this context mediates bone marrow myeloid precursor activation and proliferation. Importantly, we could demonstrate that the 'recognition' of Western dieting by NLRP3 led to a long-lasting change of cellular responsiveness towards a range of innate immune-activating stimuli in innate immune cells and their myeloid precursors. Thus, we identified that NLRP3 can provoke 'innate immune memory', which could be of importance for the development of chronic inflammatory conditions in metabolic diseases linked to Western diets.
Identifying the exact molecular mechanisms that trigger inflammasome activation by many different activators, however, remains particularly challenging. As of yet, the exact molecular details of NLRP3 activation remain not fully understood. However, our systems pharmacology and proteomics approach combined with novel biochemical techniques led to a better understanding of how NLRP3 is activated.