OTULIN haploinsufficiency predisposes to environmentally directed inflammation

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• OTULIN haploinsufficiency is associated with increased susceptibility to Staphylococcus aureus infections and local necrosis.
• Patient pathogenesis differs from classical OTULIN-related autoinflammatory syndrome (ORAS), with no observed immunological abnormalities.
• Previous findings suggested a non-hematopoietic basis for OTULIN haploinsufficiency in humans.

Purpose of the Study:

• To investigate the role of hematopoietic-driven inflammation in OTULIN haploinsufficiency using a mouse model.
• To explore the cellular and molecular mechanisms underlying inflammation in OTULIN haploinsufficiency.

Main Methods:

• Utilized an Otulin mouse model subjected to in vivo lipopolysaccharide (LPS) provocation.
• Analyzed inflammatory signatures, focusing on CD64+ monocytes and macrophages.
• Performed in vitro stimulation of bone marrow-derived macrophages (BMDMs) with LPS and polyinosinic:polycytidylic acid (Poly(I:C)).
• Conducted experiments using full and mixed bone marrow chimeric mice.

Main Results:

• LPS-provoked Otulin mice exhibited a hyperinflammatory signature driven by CD64+ monocytes and macrophages.
• Otulin BMDMs showed increased proinflammatory cytokine secretion upon in vitro stimulation.
• Experiments in chimeric mice indicated that inflammation was primarily driven by the hematopoietic compartment in mice, contrasting with human observations.

Conclusions:

• OTULIN plays a crucial role in regulating environmentally directed inflammation.
• In mice, OTULIN haploinsufficiency-associated inflammation is largely driven by the hematopoietic system, with cell-extrinsic effects contributing.
• Findings highlight species-specific differences in the pathogenesis of OTULIN haploinsufficiency.