Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction

Marc Jonathan George; Nur Hayati Jasmin; Valerie Taylor Cummings; Angela Richard-Loendt; Francesca Launchbury; Kevin Woollard; Tabitha Turner-Stokes; Ana Isabel Garcia Diaz; Mark Lythgoe; Daniel James Stuckey; Aroon Dinesh Hingorani; Derek William Gilroy

doi:10.1016/j.jacbts.2021.01.013

Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction

JACC Basic Transl Sci. 2021 Apr 7;6(5):431-443. doi: 10.1016/j.jacbts.2021.01.013. eCollection 2021 May.

Authors

Affiliations

¹ Department of Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.
² Department of Clinical Pharmacology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
³ Centre for Advanced Biomedical Imaging (CABI), Division of Medicine, University College London, London, United Kingdom.
⁴ Department of Neuropathology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
⁵ UCL IQPath, Institute of Neurology, University College London, London, United Kingdom.
⁶ Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, United Kingdom.
⁷ Centre for Translational Genomics, Institute of Cardiovascular Science, University College London, London, United Kingdom.

Abstract

Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti-IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI.

Keywords: AAR, area at risk; Ab, antibody; CCL, C-C motif chemokine ligand; CMR, cardiac magnetic resonance; CXCL, C-X-C motif ligand; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; IS, infarct size; LGE, late-gadolinium enhancement; LVEF, left ventricular ejection fraction; MHC, major histocompatibility complex; MI, myocardial infarction; NSTEMI, non–ST-segment-elevation MI; RCAEC, rat coronary artery endothelial cell; STEMI, ST-segment-elevation MI; TCZ, tocilizumab; Trop-T, troponin T; c-caspase-3, cleaved caspase-3; inflammation; interleukin-6; myocardial infarction; reperfusion; sIL-6R, soluble IL-6 receptor.

Abstract

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