AUTHOR=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 

TITLE=OTULIN haploinsufficiency predisposes to environmentally directed inflammation

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.983686

DOI=10.3389/fimmu.2024.983686

ISSN=1664-3224

ABSTRACT=<p>Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to <italic>Staphylococcus aureus</italic> 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 <italic>S. aureus</italic> 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 <italic>Otulin<sup>+/−</sup></italic> mouse model after <italic>in vivo</italic> provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked <italic>Otulin<sup>+/−</sup></italic> mice, which was driven by CD64<sup>+</sup> monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of <italic>Otulin<sup>+/−</sup></italic> mice demonstrated higher proinflammatory cytokine secretion after <italic>in vitro</italic> 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.</p>