Elena Wagner

BACKGROUND: Abdominal aortic aneurysms (AAAs) are characterized by ECM (extracellular matrix) degradation and chronic vascular inflammation, with macrophages playing a key role. The mechanisms regulating macrophage activation in AAA remain incompletely understood. Vascular macrophages express Olfr2 (olfactory receptor 2), a GPCR (G-protein–coupled receptor) implicated in inflammation, but its role in AAA development is unknown. METHODS: We investigated the role of Olfr2 in AAA using PPE (porcine pancreatic elastase) infusion in Olfr2-deficient ( Olfr2 ^−/− ), Ang II (angiotensin II) infusion in Apoe ^−/− Olfr2 ^−/− mice, bone marrow transplantation, and pharmacological modulation experiments. Echocardiography and histology were complemented by spectral flow cytometry, transcriptional profiling, and functional in vivo and ex vivo assays. RESULTS: Microarray analysis revealed increased expression of the human Olfr2 orthologue OR6A2 (olfactory receptor family 6 subfamily A member 2) in AAA tissue. Flow cytometry showed OR6A2 upregulation in monocytes from patients with large versus small AAAs. In both human and murine tissues, up to 30% of vascular macrophages expressed OR6A2/Olfr2, which peaked in MHCII ^high CCR2 ^low monocytes/macrophages on day 7 of experimental AAA. Both whole-body and hematopoietic Olfr2 deficiency protected mice from AAA formation, with reduced ECM degradation, decreased macrophage infiltration, and preserved smooth muscle cell content. Treatment with the Olfr2 agonist octanal exacerbated, while the antagonist citral reduced AAA and inflammation. In Olfr2 ^−/− mice, inflammatory gene expression and aortic leukocyte accumulation were diminished. Despite a similar total leukocyte count, Ly6C ^high monocytes displayed reduced CX3CR1 (CX3C motif chemokine receptor 1) expression and impaired migration toward CX3CL1 in vitro. Competitive transfer confirmed reduced migratory capacity of Olfr2 ^−/− monocytes, while pharmacological CX3CR1 inhibition mitigated the proinflammatory effects of octanal in AAA. CONCLUSIONS: Olfr2 regulates monocyte recruitment and macrophage-driven inflammation during AAA. Its genetic deletion or pharmacological inhibition protects against AAA, whereas receptor activation worsens the disease. Olfr2 represents a critical modulator of vascular inflammation and a potential therapeutic target in AAA.

Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes ( Hoip ^A-KO ) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8–mediated cell death is sufficient to prevent lipodystrophy and MASLD in Hoip ^A-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death–driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome.