Dysregulated NADPH Oxidase Promotes Bone Damage in Murine Model of Autoinflammatory Osteomyelitis

J Immunol. 2020 Mar 15;204(6):1607-1620. doi: 10.4049/jimmunol.1900953. Epub 2020 Feb 5.

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. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Bone and Bones / immunology
  • Bone and Bones / pathology*
  • Cell Line
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Disease Models, Animal
  • Humans
  • Interleukin-1beta / immunology
  • Interleukin-1beta / metabolism
  • Mice
  • Mice, Transgenic
  • Mutation
  • NADPH Oxidase 2 / genetics
  • NADPH Oxidase 2 / metabolism*
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Osteomyelitis / genetics
  • Osteomyelitis / immunology*
  • Osteomyelitis / pathology
  • Primary Cell Culture
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Superoxides / immunology
  • Superoxides / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • IL1B protein, mouse
  • Interleukin-1beta
  • Pstpip2 protein, mouse
  • Superoxides
  • Cybb protein, mouse
  • NADPH Oxidase 2

Supplementary concepts

  • Chronic recurrent multifocal osteomyelitis