Selective inhibition of soluble tumor necrosis factor signaling reduces abdominal aortic aneurysm progression

Silke Griepke; Emilie Grupe; Jes Sanddal Lindholt; Elizabeth Hvitfeldt Fuglsang; Lasse Bach Steffensen; Hans Christian Beck; Mia Dupont Larsen; Sissel Karoline Bang-Møller; Martin Overgaard; Lars Melholt Rasmussen; Kate Lykke Lambertsen; Jane Stubbe

doi:10.3389/fcvm.2022.942342

Selective inhibition of soluble tumor necrosis factor signaling reduces abdominal aortic aneurysm progression

Front Cardiovasc Med. 2022 Sep 16:9:942342. doi: 10.3389/fcvm.2022.942342. eCollection 2022.

Authors

Silke Griepke¹, Emilie Grupe¹, Jes Sanddal Lindholt^{2

3}, Elizabeth Hvitfeldt Fuglsang¹, Lasse Bach Steffensen¹, Hans Christian Beck^{2

4}, Mia Dupont Larsen¹, Sissel Karoline Bang-Møller¹, Martin Overgaard^{2

4}, Lars Melholt Rasmussen^{2

4}, Kate Lykke Lambertsen^{5

6

7}, Jane Stubbe^{1

2}

Affiliations

¹ Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
² Elite Research Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
³ Department of Cardiothoracic and Vascular Surgery, Odense University Hospital, Odense, Denmark.
⁴ Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
⁵ Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
⁶ Department of Neurology, Odense University Hospital, Odense, Denmark.
⁷ BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

Abstract

Background: Tumor necrosis factor (TNF) is pathologically elevated in human abdominal aortic aneurysms (AAA). Non-selective TNF inhibition-based therapeutics are approved for human use but have been linked to several side effects. Compounds that target the proinflammatory soluble form of TNF (solTNF) but preserve the immunomodulatory capabilities of the transmembrane form of TNF (tmTNF) may prevent these side effects. We hypothesize that inhibition of solTNF signaling prevents AAA expansion.

Methods: The effect of the selective solTNF inhibitor, XPro1595, and the non-selective TNF inhibitor, Etanercept (ETN) was examined in porcine pancreatic elastase (PPE) induced AAA mice, and findings with XPro1595 was confirmed in angiotensin II (ANGII) induced AAA in hyperlipidemic apolipoprotein E (Apoe) ^-/- mice.

Results: XPro1595 treatment significantly reduced AAA expansion in both models, and a similar trend (p = 0.06) was observed in PPE-induced AAA in ETN-treated mice. In the PPE aneurysm wall, XPro1595 improved elastin integrity scores. In aneurysms, mean TNFR1 levels reduced non-significantly (p = 0.07) by 50% after TNF inhibition, but the histological location in murine AAAs was unaffected and similar to that in human AAAs. Semi-quantification of infiltrating leucocytes, macrophages, T-cells, and neutrophils in the aneurysm wall were unaffected by TNF inhibition. XPro1595 increased systemic TNF levels, while ETN increased systemic IL-10 levels. In ANGII-induced AAA mice, XPro1595 increased systemic TNF and IL-5 levels. In early AAA development, proteomic analyses revealed that XPro1595 significantly upregulated ontology terms including "platelet aggregation" and "coagulation" related to the fibrinogen complex, from which several proteins were among the top regulated proteins. Downregulated ontology terms were associated with metabolic processes.

Conclusion: In conclusion, selective inhibition of solTNF signaling reduced aneurysm expansion in mice, supporting its potential as an attractive treatment option for AAA patients.

Keywords: abdominal aortic aneurysm; cardiovascular disease; inflammation; translational research; tumor necrosis factor inhibitor; vascular inflammation.