Investigation of inflammasome regulation: the influence of priming and CARD-only proteins

However, conflicting studies suggest that COPs, including CARD16, can promote inflammasome activation so the role of these proteins remains unclear.<br><br>The data presented here show successful differentiation of iMacs that express high levels of macrophage-specific markers, display macrophage-like phagocytic activity, and respond robustly to a wide range of inflammasome stimuli. In addition, iPSC-derived myeloid precursor cells were differentiated into iPSC-derived microglia that displayed significant NLRP3 activity.

In addition priming through different TLR pathways was shown to influence both NLRP1 and NLRP3 responses through IFN signalling. LPS-induced IFN signalling limited NLRP3 and NLRP1 activation in a time-dependent manner. This effect was dependent on IL-10 and to a lesser extent STAT3.<br><br>However, mass spectrometry experiments revealed that LPS-induced IFN signalling did not regulate inflammasome activity through altering inflammasome-related protein expression, suggesting a role for transcription-independent mechanisms.

Finally, CARD16 was shown to increase NLRP3 and NLRP1 inflammasome activation in a time-dependent manner. CARD16 also regulated cytokine secretion in an NF-κBindependent manner, suggesting a role for CARD16 in the regulation of other transcription factors.<br><br><i>Thesis is embargoed until 31 December 2026</i>.<br><br>