Regulation of neutrophil NADPH oxidase by PSTPIP2 affects bone damage in murine autoinflammatory osteomyelitis
Kralova, J.; Drobek, A.; Prochazka, J.; Spoutil, F.; Glatzova, D.; Borna, S.; Pokorna, J.; Skopcova, T.; Angelisova, P.; Gregor, M.; Kovarik, P.; Sedlacek, R.; Brdicka, T.
Show abstract
Autoinflammatory diseases are characterized by dysregulation of the innate immune system leading to spontaneous inflammation. Pstpip2cmo mouse strain is a well-characterized model of this class of disorders. Due to the mutation leading to the lack of adaptor protein PSTPIP2, these animals suffer from autoinflammatory chronic multifocal osteomyelitis similar to several human syndromes. Current evidence suggests that it is driven by hyperproduction of IL-1{beta} by neutrophil granulocytes. Here we show that in addition to IL-1{beta}, PSTPIP2 also negatively regulates ROS generation by neutrophil NADPH oxidase. Pstpip2cmo neutrophils display highly elevated ROS production in response to a range of stimuli. Inactivation of NADPH oxidase in Pstpip2cmo mice did not affect IL-1{beta} levels and the autoinflammatory process was initiated with similar kinetics. However, the bone destruction was almost completely alleviated, suggesting that dysregulated NADPH oxidase activity is a key factor promoting autoinflammatory bone damage in Pstpip2cmo mice.
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