Leukocyte-Associated Immunoglobulin-like Receptor-1 is regulated in human myocardial infarction but its absence does not affect infarct size in mice

Leo Timmers,Marie-José T H Goumans,Gerard Pasterkamp,Maike A D Brans,Sanne De Jong,Bas R Van Klarenbosch,Mirjam B Smeets,Judith J De Haan,Imo E Hoefer,Saskia C A De Jager,Linde Meyaard,Fatih Arslan,Sander M Van De Weg,Pieter A Doevendans,Guilielmus H J M Ellenbroek

doi:10.1038/s41598-017-13678-5

Abstract

Heart failure after myocardial infarction (MI) depends on infarct size and adverse left ventricular (LV) remodelling, both influenced by the inflammatory response. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is an inhibitory receptor of ITAM-dependent cell activation, present on almost all immune cells. We investigated regulation of LAIR-1 leukocyte expression after MI in patients and hypothesized that its absence in a mouse model of MI would increase infarct size and adverse remodelling. In patients, LAIR-1 expression was increased 3 days compared to 6 weeks after MI on circulating monocytes (24.8 ± 5.3 vs. 21.2 ± 5.1 MFI, p = 0.008) and neutrophils (12.9 ± 4.7 vs. 10.6 ± 3.1 MFI, p = 0.046). In WT and LAIR-1−/− mice, infarct size after ischemia-reperfusion injury was comparable (37.0 ± 14.5 in WT vs. 39.4 ± 12.2% of the area at risk in LAIR-1−/−, p = 0.63). Remodelling after permanent left coronary artery ligation did not differ between WT and LAIR-1−/− mice (end-diastolic volume 133.3 ± 19.3 vs. 132.1 ± 27.9 μL, p = 0.91 and end-systolic volume 112.1 ± 22.2 vs. 106.9 ± 33.5 μL, p = 0.68). Similarly, no differences were observed in inflammatory cell influx or fibrosis. In conclusion, LAIR-1 expression on monocytes and neutrophils is increased in the acute phase after MI in patients, but the absence of LAIR-1 in mice does not influence infarct size, inflammation, fibrosis or adverse cardiac remodelling.

Highlights

Heart failure (HF) is a complex clinical syndrome and is often caused by reduced cardiac pump function, affecting approximately 1–2% of people in the Western world[1]
The transmembrane expression of Leukocyte-associated immunoglobulinlike receptor 1 (LAIR-1) on monocytes was significantly higher in the acute phase (3 days after myocardial infarction (MI)), compared to the chronic phase (24.8 ± 5.3 at day 3 vs. 21.2 ± 5.1 MFI at 6 weeks post MI, p = 0.008; Fig. 2a), and both were significantly increased with respect to healthy controls
LAIR-1 is present on a variety of immune cells[14] and important in the regulation of leukocyte activation in response to an inflammatory reaction[15,26,27]

Summary

Introduction

Heart failure (HF) is a complex clinical syndrome and is often caused by reduced cardiac pump function, affecting approximately 1–2% of people in the Western world[1]. In the chronic phase, activated and pro-inflammatory monocytes and T-lymphocytes increase adverse remodelling, which leads to impaired cardiac function[11,12]. In both processes, leukocyte activation is key and regulated by integration of signals from activating and inhibitory cell-receptors[13]. The majority of immune inhibitory receptors contain intracellular domains that – upon activation – are able to down regulate or inhibit activation signals from stimulating receptors Thereby, they increase the threshold for leukocytes to become activated and attenuate pro-inflammatory effects. We studied the effect of LAIR-1 deficiency in experimental MI in mice, measuring inflammation, infarct size, adverse left ventricular remodelling and cardiac function

Methods

Results

Conclusion