OTULIN haploinsufficiency predisposes to environmentally directed inflammation

Front Immunol. 2024 May 21:15:983686. doi: 10.3389/fimmu.2024.983686. eCollection 2024.

Abstract

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.

Keywords: OTULIN; OTULIN deficiency; OTULIN-related autoinflammatory syndrome; inborn errors in immunity; inflammation.

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Haploinsufficiency*
  • Humans
  • Inflammation* / genetics
  • Lipopolysaccharides*
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C

Substances

  • Lipopolysaccharides
  • Cytokines
  • Poly I-C

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. FS (11B5520N) and JN (11C3521N) are fellows of the Fonds Wetenschappelijk Onderzoek - Vlaanderen National Fund for Scientific Research (FWO). RS is FWO senior clinical investigator fellows (1805518N, respectively) and received funding from KU Leuven C1 (C12/16/024). This work was supported by the VIB Grand Challenges Program and the KU Leuven BOFZAP start-up grant (to SH-B). VM (11I7523NI) and LS (1186121N) are fellows of the Fonds Wetenschappelijk onderzoek - Vlaanderen National Fund for Scientific Research (FWO). MGe received funding from the Belgian Kids' Fund.