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. Because of 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-1β by neutrophil granulocytes. In this study, we show that in addition to IL-1β, PSTPIP2 also negatively regulates pathways governing reactive oxygen species generation by neutrophil NOX2 NADPH oxidase. Pstpip2cmo neutrophils display highly elevated superoxide production in response to a range of stimuli. Inactivation of NOX2 NADPH oxidase in Pstpip2cmo mice did not affect IL-1β 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.

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences 25242 Vestec Czech Republic

Faculty of Science Charles University 12800 Prague Czech Republic

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences 14220 Prague Czech Republic

Laboratory of Integrative Biology Institute of Molecular Genetics of the Czech Academy of Sciences 14220 Prague Czech Republic; and

Laboratory of Leukocyte Signalling Institute of Molecular Genetics of the Czech Academy of Sciences 14220 Prague Czech Republic

Laboratory of Leukocyte Signalling Institute of Molecular Genetics of the Czech Academy of Sciences 14220 Prague Czech Republic;

Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences 25242 Vestec Czech Republic

Max F Perutz Laboratories University of Vienna 1030 Vienna Austria

Citace poskytuje Crossref.org

Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation

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