Lipocalin‐2 Promotes M1 Macrophages Polarization in a Mouse Cardiac Ischaemia–Reperfusion Injury Model

Abstract

Ischaemia-reperfusion (IR) injury is a major issue in cardiac transplantation. Inflammatory processes play a major role in myocardial IR injury. Lipocalin-2 (Lcn2), which is also known as neutrophil gelatinase-associated lipocalin, has multiple functions that include the regulation of cell death/survival, cell migration/invasion, cell differentiation and iron delivery. In our study, the hearts of C57BL/6 mice were flushed with and stored in cold Bretschneider solution for 8 h and then transplanted into a syngeneic recipient. We found that Lcn2 neutralization decreased the recruitment of neutrophils and macrophages. Troponin T (TnT) production, 24 h after myocardial IR injury, was reduced through anti-Lcn2 antibody administration. The cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts administrated with antiLcn2 antibody administration (anti-Lcn-2: 58.9 AE 5.62 ml/min; control: 25.8 AE 4.1 ml/min; P < 0.05). Anti-Lcn2 antibody treatment suppressed M1 marker (IL-12, IL-23 and iNOS) expression but increased M2 marker (IL-10, Arg1 and Mrc1) expression. Furthermore, in our vitro and vivo experiments, we found that anti-Lcn2 antibody treatment failed to induce M1-related gene expression in response to LPS and that Lcn2 neutralization enhanced the expression of M2-related genes following IL-4 treatment. In conclusion, Lcn2 promotes M1 polarization, and Lcn2 neutralization attenuates cardiac IR injury.

More than a simple biomarker: the role of NGAL in cardiovascular and renal diseases

“…and MCP-1 (5). Finally, it has been shown that NGAL was involved in the polarization of macrophages towards the pro-inflammatory phenotype M1, in vitro and in vivo (89,109).…”

“…In addition, increasing NGAL circulating levels of NGAL KO mice using an NGAL encoding adenovirus treatment resulted in impaired cardiac functional recovery and decreased mitochondrial function of the isolated-perfused hearts (90). In a mouse model of I/R after heart transplantation, the use of anti-NGAL antibodies reduced the infiltration of macrophages and neutrophils into the ischemic zone, suppressed the M1 polarization of macrophages, and blunted the I/R-induced cardiac lesions (89).…”

The divergent roles of macrophages in solid organ transplantation

“…A recent study revealed lipocalin2 (Lcn2), a defense mediator expressed in response to TLR activation, plays a crucial role in cardiac IRI, and neutralization of Lcn2 suppressed M1 macrophage polarization and instead mediated skewing of macrophages toward an M2 phenotype. Additionally, Lcn2 treatment suppressed infiltration of macrophages further limiting IRI [36]. …”

Protective effect of microRNA-138 against cerebral ischemia/reperfusion injury in rats

“…The expression of Lcn-2 is markedly upregulated in injured spinal cord and brain tissue (13,14). The involvement of Lcn-2 in the systemic response to IR has been documented in previous studies of the heart and kidneys (15)(16)(17).…”

“…It is speculated that oxidative radical-induced inflammation is crucially involved during the progression of CIR injury (17). Since miRs were identified as common regulators of DNA transcription and mRNA translation, numerous miRs have been associated with oxidative radical-mediated pathophysiological alterations (19).…”