Sustained hyper-activation of the NLRP3 inflammasome protein complex
and the overproduction of pro-inflammatory cytokines like IL-1β are
characteristic features of autoinflammatory diseases. For the activation of
such inflammatory pathways the importance of reactive oxygen species
(ROS) is well established. However, less is known about the interaction of
the two major cellular ROS producing systems (NADPH oxidases and
mitochondria), which presumably is dependent on exogenous stimuli and
cellular context. We and others have found that in patients and mice lacking
functional NADPH oxidase 2 (NOX2) higher levels of IL-1β are detectable
and lead to an impairment of the hematopoietic stem cell pool in the bone
marrow. We now want to examine,
1. whether this exhaustion of hematopoietic cells with long-term
repopulation capacities also applies for other autoinflammatory
diseases like cryopyrin associated periodic fever syndromes, Familiar
Mediterranean Fever, or systemic juvenile idiopathic arthritis.
2. how ROS derived from NOX2 and mitochondria interfere/cooperate
during the inflammasome activation in different cellular systems.