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Abstract

Inflammatory bowel disease (IBD) is characterized by severe and recurrent inflammation of the gastrointestinal tract, associated with altered patterns of cytokine synthesis, excessive reactive oxygen species (ROS) production, and high levels of the innate immune protein, lipocalin-2 (LCN-2), in the mucosa. The major source of ROS in intestinal epithelial cells is the NADPH oxidase NOX1, which consists of the transmembrane proteins, NOX1 and p22PHOX, and the cytosolic proteins, NOXO1, NOXA1, and Rac1. Here, we investigated whether NOX1 activation and ROS production induced by key inflammatory cytokines in IBD causally affects LCN-2 production in colonic epithelial cells. We found that the combination of TNFα and IL-17 induced a dramatic upregulation of NOXO1 expression that was dependent on the activation of p38MAPK and JNK1/2, and resulted into an increase of NOX1 activity and ROS production. NOX1-derived ROS drive the expression of LCN-2 by controlling the expression of IκBζ, a master inducer of LCN-2. Furthermore, LCN-2 production and colon damage were decreased in NOX1-deficient mice during TNBS-induced colitis. Finally, analyses of biopsies from patients with Crohn’s disease showed increased JNK1/2 activation, and NOXO1 and LCN-2 expression. Therefore, NOX1 might play a key role in mucosal immunity and inflammation by controlling LCN-2 expression.

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Acknowledgements

The authors wish to thank Dr. Martine Torres for her editorial help, Pr. Anne Couvelard for the histological images of the colon sections, and Olivier Thibaudeau for preparation of the paraffin sections. This work was supported by La Ligue Nationale Contre le Cancer, Comité De Paris, Grant no. RS17/75-46, and no. RS18/75-13, INSERM, CNRS and University Denis-Diderot Paris 7.

Author information

Author notes

  1. These authors contributed equally: Nesrine Makhezer, Marwa Ben Khemis, Dan Liu

Affiliations

  1. INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l’Inflammation, Paris, France

    • Nesrine Makhezer
    • , Marwa Ben Khemis
    • , Dan Liu
    • , Yamina Khichane
    • , Viviana Marzaioli
    • , Asma Tlili
    • , Marjan Mojallali
    • , Coralie Pintard
    • , Philippe Letteron
    • , Margarita Hurtado-Nedelec
    • , Jamel El-Benna
    • , Jean-Claude Marie
    •  & Pham My-Chan Dang
  2. Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d’Excellence Inflamex, DHU FIRE, Faculté de Médecine, Site Xavier Bichat, Paris, France

    • Nesrine Makhezer
    • , Marwa Ben Khemis
    • , Dan Liu
    • , Yamina Khichane
    • , Viviana Marzaioli
    • , Asma Tlili
    • , Marjan Mojallali
    • , Coralie Pintard
    • , Philippe Letteron
    • , Margarita Hurtado-Nedelec
    • , Jamel El-Benna
    • , Jean-Claude Marie
    •  & Pham My-Chan Dang
  3. Département d’Immunologie et d’Hématologie, UF Dysfonctionnements Immunitaires, HUPNVS, Hôpital Bichat, Paris, France

    • Margarita Hurtado-Nedelec
  4. Département de Pathologie, Hôpital Bichat – Claude Bernard, Paris, France

    • Aurélie Sannier
  5. Service d’Hépato-Gastroentérologie et Cancérologie Digestive, Hôpital Bichat – Claude Bernard, Paris, France

    • Anne-Laure Pelletier

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Contributions

N.M., M.B.K., D.L., Y.K., A.T., M.M., C.P., P.L., and A.S. designed and performed the experiments and analyzed the data. V.M., M.H.N., J.C.M., and J.E.B. analyzed the data and contributed to the critical reading of the manuscript. A.L.P. recruited the patients, contributed to the discussion, and to the critical reading of the manuscript. P.M.C.D. supervised the project, designed the experiments, and wrote the manuscript. All the authors have read the manuscript and agreed with the data.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Pham My-Chan Dang.

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DOI

https://doi.org/10.1038/s41385-018-0086-4