Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality.

Abstract

Aims:

Macrophage phagocytosis of dead cells is a prerequisite for inflammation resolution. Because CXCL4 induces macrophage phagocytosis in vitro, we examined the impact of exogenous CXCL4 infusion on cardiac wound healing and macrophage phagocytosis following myocardial infarction (MI).

Methods and results:

CXCL4 expression significantly increased in the infarct region beginning at Day 3 post-MI, and macrophages were the predominant source. Adult male C57BL/6J mice were subjected to coronary artery occlusion, and MI mice were randomly infused with recombinant mouse CXCL4 or saline beginning at 24 h post-MI by mini-pump infusion. Compared with saline controls, CXCL4 infusion dramatically reduced 7 day post-MI survival [10% (3/30) for CXCL4 vs. 47% (7/15) for saline, P < 0.05] as a result of acute congestive heart failure. By echocardiography, CXCL4 significantly increased left ventricular (LV) volumes and dimensions at Day 5 post-MI (all P < 0.05), despite similar infarct areas compared with saline controls. While macrophage numbers were similar at Day 5 post-MI, CXCL4 infusion increased Ccr4 and Itgb4 and decreased Adamts8 gene levels in the infarct region, all of which linked to CXCL4-mediated cardiac dilation. Isolated Day 5 post-MI macrophages exhibited comparable levels of M1 and M4 markers between saline and CXCL4 groups. Interestingly, by both ex vivo and in vitro phagocytosis assays, CXCL4 reduced macrophage phagocytic capacity, which was connected to decreased levels of the phagocytosis receptor CD36. In vitro, a CD36 neutralizing antibody (CD36Ab) significantly inhibited macrophage phagocytic capacity. The combination of CXCL4 and CD36Ab did not have an additive effect, indicating that CXCL4 regulated phagocytosis through CD36 signalling. CXCL4 infusion significantly elevated infarct matrix metalloproteinase (MMP)-9 levels at Day 5 post-MI, and MMP-9 can cleave CD36 as a down-regulation mechanism.

Conclusion:

CXCL4 infusion impaired macrophage phagocytic capacity by reducing CD36 levels through MMP-9 dependent and independent signalling, leading to higher mortality and LV dilation.

• Authors: Merry L Lindsey, Mira Jung, Andriy Yabluchanskiy, Presley L Cannon, Rugmani Padmanabhan Iyer, Elizabeth R Flynn, Kristine Y DeLeon-Pennell, Fritz M Valerio, Courtney L Harrison, Crystal M Ripplinger, Michael E Hall, Yonggang Ma
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 115 Issue 2 Pg. 395-408 (02 01 2019) ISSN: 1755-3245 [Electronic] England
• PMID: 30169632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• CD36 Antigens
• Cd36 protein, mouse
• Integrin beta4
• Platelet Factor 4
• ADAMTS Proteins
• Adamts8 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• ADAMTS Proteins (metabolism)
• Animals
• CD36 Antigens (metabolism)
• Cells, Cultured
• Disease Models, Animal
• Humans
• Hypertrophy, Left Ventricular (chemically induced, metabolism, pathology, physiopathology)
• Infusions, Subcutaneous
• Integrin beta4 (metabolism)
• Macrophages, Peritoneal (drug effects, metabolism, pathology)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice, Inbred C57BL
• Myocardial Infarction (drug therapy, metabolism, pathology, physiopathology)
• Myocardium (metabolism, pathology)
• Phagocytosis (drug effects)
• Platelet Factor 4 (administration & dosage, metabolism, toxicity)
• Signal Transduction
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)