Frontiers in Immunology (May 2024)

OTULIN haploinsufficiency predisposes to environmentally directed inflammation

  • Frederik Staels,
  • Frederik Staels,
  • Leoni Bücken,
  • Leana De Vuyst,
  • Mathijs Willemsen,
  • Erika Van Nieuwenhove,
  • Margaux Gerbaux,
  • Julika Neumann,
  • Julika Neumann,
  • Vanshika Malviya,
  • Lize Van Meerbeeck,
  • Jeason Haughton,
  • Laura Seldeslachts,
  • Mieke Gouwy,
  • Kimberly Martinod,
  • Greetje Vande Velde,
  • Paul Proost,
  • Lidia Yshii,
  • Susan Schlenner,
  • Rik Schrijvers,
  • Rik Schrijvers,
  • Rik Schrijvers,
  • Adrian Liston,
  • Stephanie Humblet-Baron

DOI
https://doi.org/10.3389/fimmu.2024.983686
Journal volume & issue
Vol. 15

Abstract

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Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to Staphylococcus aureus infections accompanied by local necrosis and systemic inflammation. The pathogenesis observed in haploinsufficient patients differs from the hyperinflammation seen in classical OTULIN-related autoinflammatory syndrome (ORAS) patients and is characterized by increased susceptibility of dermal fibroblasts to S. aureus alpha toxin-inflicted cytotoxic damage. Immunological abnormalities were not observed in OTULIN haploinsufficient patients, suggesting a non-hematopoietic basis. In this research report, we investigated an Otulin+/− mouse model after in vivo provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked Otulin+/− mice, which was driven by CD64+ monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of Otulin+/− mice demonstrated higher proinflammatory cytokine secretion after in vitro stimulation with LPS or polyinosinic:polycytidylic acid (Poly(I:C)). Our experiments in full and mixed bone marrow chimeric mice suggest that, in contrast to humans, the observed inflammation was mainly driven by the hematopoietic compartment with cell-extrinsic effects likely contributing to inflammatory outcomes. Using an OTULIN haploinsufficient mouse model, we validated the role of OTULIN in the regulation of environmentally directed inflammation.

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