Details

Autor(en) / Beteiligte

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

Titel

OTULIN haploinsufficiency predisposes to environmentally directed inflammation

Ist Teil von

• Frontiers in immunology, 2024-05, Vol.15, p.983686

Ort / Verlag

Switzerland: Frontiers Media S.A

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to 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 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 mouse model after provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked mice, which was driven by CD64 monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of mice demonstrated higher proinflammatory cytokine secretion after 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.