Macrophages in the Inflammatory Phase following Myocardial Infarction: Role of Exogenous Ubiquitin

Figures

• 

  Figure 1. Macrophage polarization post-MI. Following MI, chemokines/cytokines released from cardiac resident and circulating immune cells are major mediators of immune cell recruitment. Monocytes stored in the bone marrow or spleen are released into circulation and migrate to the heart. At the area of injury, monocytes differentiate to macrophages and can be polarized into a range of phenotypes. M1 macrophages produce pro-inflammatory mediators, work in the initial wound clearance of apoptotic cells via efferocytosis and degrade ECM. M2 macrophages produce anti-inflammatory mediators, interact with fibroblasts, and promote wound healing.

• 

  Figure 2. Macrophage migration post-MI. Following MI, expression of chemokines/cytokines such as IL-1, IL-6, TNF-α, and CCL2 initiates migration of immune cells to the area of infarct. CCL2, one of the major chemokine mediators in monocyte migration to the heart post-MI, signals through the CCR2 receptor. Integrins are essential to the migration process. The internalization of integrin β1 can activate FAK-Src/PyK2-Rac, leading to alterations in actin polymerization and the resultant cell movement. Akt2 activation may affect actin polymerization through the phosphorylation of PKCζ and LIMK/cofilin, thereby affecting chemotaxis. Migration is essential for immune cell recruitment to the heart post-MI.

• 

  Figure 3. Macrophage efferocytosis post-MI. Following MI, macrophages are the key cell-type to remove apoptotic cells through a process termed efferocytosis. Apoptotic cells recruit macrophages via “find me” signals, such as fractalkine, uridine triphosphate, adenosine triphosphate, and sphingosine-1-phosphate. Then, macrophages use “eat me” signals, like phosphatidylserine, to attach to the apoptotic cell. Bridging molecules including protein S, Gas6, and milk fat globule-EGF factor 8 (MFGE8) further aid in tethering the apoptotic cell to the macrophage. Macrophage receptors (such as myeloid epithelial-reproductive tyrosine kinase (MERTK), CD14, receptor tyrosine kinases (RTKs), scavenger receptor A and scavenger receptor B (CD36)) for efferocytosis recognize apoptotic cells. After recruitment, recognition, and tethering, macrophages engulf apoptotic cells into phagosomes, which mature into phagolysosomes to digest cellular debris.

• 

  Figure 4. Proposed role of eUB in phenotype and function of macrophages in the heart post-MI. In THP-1 monocytes, eUB/CXCR4 signaling can potentially activate phospholipase Cβ (PLC), promote intracellular Ca2+ flux and reduce cAMP levels. eUB/CXCR4 axis can activate RSK1, Akt, and ERK, and influence migration. In M0 macrophages, eUB affects expression of genes associated with M1 and M2 polarization.