Frontiers in immunology · 2025
Hyaluronan synthase 3 deficiency lowers the incidence of ruptures of abdominal aortic aneurysms by reducing monocyte infiltration.
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Niemann Viola, Brack Fedor, Rolauer Luca, Kaczur Janet, Petzsch Patrick, Köhrer Karl, Quast Christine, Gerdes Norbert, Bouvain Pascal, Voigt Katharina, Krüger Martina, Brückner Alexander, Fleischmann Bernd K, Wenzel Daniela, Barnowski Philipp, Zimmermann Laura-Marie, Simsekyilmaz Sakine, Filler Timm, Ibing Wiebke, Feige Tobias, Krott Kim J, Wagenhäuser Markus U, Fischer Jens W, Elvers Margitta, Sengle Gerhard, Flögel Ulrich, Hundhausen Christian, Suvorava Tatsiana, Grandoch Maria
Аннотация
INTRODUCTION: Abdominal aortic aneurysms and dissections (AAA/AD) are vascular disorders with high mortality due to aortic ruptures. Critical pathomechanisms involve immune cell infiltration and degradation of the vascular extracellular matrix (ECM). Hyaluronan (HA), a major constituent of the ECM synthesized by three HA synthase isoenzymes (HAS1-3), plays a role in both processes. Specifically, HAS3 is crucially involved in inflammatory conditions. Here, we aimed to elucidate the role of HAS3-derived HA in AAA/AD.
METHODS: Mice double-deficient for apolipoprotein E and Has3 (Apoe/Has3-DKO) and littermate controls (Apoe-KO) were studied in a model of angiotensin II (AngII)-induced AAA/AD.
RESULTS: Has3 deficiency improved survival in Apoe/Has3-DKO mice via reducing aortic ruptures. This was associated with decreased monocyte infiltration into the vessel wall. Aortic RNA-Seq analysis indicated disturbed immune cell adhesion and diapedesis. Transfer of Apoe-deficient bone marrow into Apoe/Has3-DKO mice largely normalized the Apoe/Has3-DKO phenotype. While gene expression in endothelial cells (ECs) was not affected, AngII-induced upregulation of proinflammatory cytokines, adhesion receptors and the HA receptor CD44 was attenuated in Apoe/Has3-DKO monocytes. This reduced CD44 cell surface expression in Apoe/Has3-double-deficient monocytes, ultimately inhibiting their in vitro transmigration.
DISCUSSION: Our results show that HAS3 plays a key role in AAA/AD formation and suggest the HAS3/CD44 axis as promising therapeutic target to reduce monocyte recruitment and aortic rupture.
METHODS: Mice double-deficient for apolipoprotein E and Has3 (Apoe/Has3-DKO) and littermate controls (Apoe-KO) were studied in a model of angiotensin II (AngII)-induced AAA/AD.
RESULTS: Has3 deficiency improved survival in Apoe/Has3-DKO mice via reducing aortic ruptures. This was associated with decreased monocyte infiltration into the vessel wall. Aortic RNA-Seq analysis indicated disturbed immune cell adhesion and diapedesis. Transfer of Apoe-deficient bone marrow into Apoe/Has3-DKO mice largely normalized the Apoe/Has3-DKO phenotype. While gene expression in endothelial cells (ECs) was not affected, AngII-induced upregulation of proinflammatory cytokines, adhesion receptors and the HA receptor CD44 was attenuated in Apoe/Has3-DKO monocytes. This reduced CD44 cell surface expression in Apoe/Has3-double-deficient monocytes, ultimately inhibiting their in vitro transmigration.
DISCUSSION: Our results show that HAS3 plays a key role in AAA/AD formation and suggest the HAS3/CD44 axis as promising therapeutic target to reduce monocyte recruitment and aortic rupture.