S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll‐like receptor 4

Abstract

Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 release. S100A1 internalization was observed in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes. In vitro analyses revealed exclusive S100A1 endocytosis by CFs, followed by Toll-like receptor 4 (TLR4)-dependent activation of MAP kinases and NF-κB. CFs exposed to S100A1 assumed an immunomodulatory and anti-fibrotic phenotype characterized i.e. by enhanced intercellular adhesion molecule-1 (ICAM1) and decreased collagen levels. In mice, intracardiac S100A1 injection recapitulated these transcriptional changes. Moreover, antibody-mediated neutralization of S100A1 enlarged infarct size and worsened left ventricular functional performance post-MI. Our study demonstrates alarmin properties for S100A1 from necrotic cardiomyocytes. However, the potentially beneficial role of extracellular S100A1 in MI-related inflammation and repair warrants further investigation.

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…The exact ligand/receptor systems that couple DAMPs to changes in fibroblast function in the injured heart are only just beginning to emerge, and recent evidence suggests the DAMPs/fibroblast axis is important in both inflammatory and fibrotic responses of the heart to damage [25,67,68]. Identification and characterisation of these systems is important for designing novel therapies for reducing post-MI damage [14,69].…”

“…At the cellular level, isolated rat and mouse cardiomyocytes express TLR2, 3, 4 and 6 [71,72], but TLR expression in fibroblasts is less well characterised. However, there is evidence for functional expression of TLR2 [57,73], TLR3 [73], TLR4 [68,73,74] and TLR9 [73,75] in CF. Of the known members of the NLR family, CF express NOD1 and NOD2 [26,62], as well as the inflammasome-associated NLRP3 [73,76] RAGE is expressed in several cell types within the heart [64] and in cultured human and rodent CF [23,[77][78][79].…”

“…Several recent studies [25,67,68] have added significant credence to the hypothesis that CF can act as sensors of cell and tissue damage in the heart, triggering both inflammatory and fibrotic responses as a consequence of passively released DAMPs from damaged cells. Moreover, CF are also able to react to changes in ECM composition, for example in response to AGE-modified collagen [23] or FN-EDA [74].…”

“…Indeed, several S100 proteins act as important DAMPs that are released from leukocytes and act on target cells primarily via TLR4 and RAGE activation [81]. S100A1 is the most abundantly expressed S100 isoform in cardiomyocytes and can be released from damaged cardiomyocytes after ischaemia/reperfusion injury, resulting in increased serum levels [68,82]. It was shown recently that cardiomyocyte-derived S100A1 is taken up by surrounding CF through endocytosis and activates MAPK/SAPK and NFB signalling pathways in CF in a TLR4/MyD88-dependent (RAGE-independent) manner [68].…”

“…S100A1 is the most abundantly expressed S100 isoform in cardiomyocytes and can be released from damaged cardiomyocytes after ischaemia/reperfusion injury, resulting in increased serum levels [68,82]. It was shown recently that cardiomyocyte-derived S100A1 is taken up by surrounding CF through endocytosis and activates MAPK/SAPK and NFB signalling pathways in CF in a TLR4/MyD88-dependent (RAGE-independent) manner [68]. S100A1 stimulated an anti-fibrotic phenotype in CF (increased expression of MMP-9 and reduced expression of collagen I, -smooth muscle actin and connective tissue growth factor) and conferred a complex immunomodulatory phenotype involving changes in both pro-and anti-inflammatory factors [68].…”