EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization

Abstract

Aims After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodeling after MI. Methods and Results Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodeling, as they exhibited lower mortality, better cardiac function, shorter scar length and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin (α-SMA) myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 (CXCR2) antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodeling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodeling during MI. Conclusion We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI. Translational Perspective We established EDIL3 as a critical regulator of neutrophil recruitment and macrophage polarization during post-MI cardiac remodeling. EDIL3 may be a candidate prognostic biomarker and drug target for cardiovascular diseases. The novel pathways and mechanisms revealed in this study has renewed our understanding of the role of leukocyte adhesion inhibitors in cardiovascular disease. Meanwhile, our study reaffirmed the indispensable role of inflammation in the healing process, thereby prompting the reevaluation of post-MI anti-inflammatory treatments.

Developmental endothelial locus-1 in cardiovascular and metabolic diseases: a promising biomarker and therapeutic target

“…In a pig model of cardiac ischemia induced by left circumflex artery ligation, DEL-1 treatment improved cardiac function [107]. Wei et al found that DEL-1 levels were decreased in severe AMI patients, which is consistent with WT mice following MI showing low levels of cardiac DEL-1 [42]. Compared with WT mice, DEL-1 -/mice showed significantly improved cardiac function and alleviated cardiac remodeling post-MI.…”

“…The study by Wei et al is the only report of amelioration of DEL-1 deficiency [42]. In previous reports, inhibition of neutrophil recruitment improved cardiac dysfunction and cardiac remodeling after MI [114][115][116].…”

“…A scar is formed to protect the left ventricle (LV) from rupture of the heart. The study by Wei et al reiterates the integral role of inflammation in the healing process [42]. However, excessive inflammation may exacerbate MI-induced myocardial injury [109,111].…”

“…Endothelial cell-derived DEL-1 mainly regulates the inflammation initiation by inhibiting neutrophil recruitment, while macrophagederived DEL-1 promotes the resolution of inflammation by enhancing neutrophil apoptosis and macrophage efferocytosis [40]. There are increasing evidences that the regulation of immune system homeostasis by DEL-1 plays an important role in CVMDs [41][42][43]. In this article, we review the regulatory role of local tissue signaling DEL-1 in CVMDs, and look forward to the future development of DEL-1 (Table 1).…”

The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior

“…Furthermore, NETs also play a significant role in atherosclerosis disease [ 13 ]. A study has confirmed that deficiency of EGF-like repeats and discoidin I-like domain 3 can improve adverse cardiac healing through polarization of pro-inflammatory macrophage which is mediated by NETs [ 14 ]. In particular, NETs are even associated with preeclampsia and central nervous system diseases [ 15 , 16 ].…”