Mechanisms of Organ Injury and Repair by Macrophages

Abstract

Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF-α, TGF-β, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Proresolving macrophages in turn restore tissue homeostasis by functioning as anti-inflammatory cells, and macrophage-derived matrix metalloproteinases regulate fibrin and collagen turnover. However, dysregulated macrophage function impairs wound healing and contributes to the development of fibrosis. Consequently, the mechanisms that regulate these different macrophage activation states have become active areas of research. In this review, we discuss the common and unique mechanisms by which macrophages instruct tissue repair in the liver, nervous system, heart, lung, skeletal muscle, and intestine and illustrate how macrophages might be exploited therapeutically.

Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation

“…During ongoing chronic injury and the progression of fibrosis, pro-inflammatory macrophages derived from monocytes prevail in the liver (12, 13, 32–34). Both monocyte-derived macrophages and Kupffer cells have profibrogenic properties, by promoting the activation and survival of HSCs and myofibroblasts through secreting both TGF-β and PDGF (33–35). Given that inflammatory macrophages can exacerbate chronic liver disease, a deeper understanding of the mechanisms by which macrophages promote inflammation and fibrosis might lead to novel strategies to treat liver diseases (12, 31, 33).…”

“…It also induces polarization of TAM to an M2-like proangiogenic phenotype, thereby promoting tumor vessel disorganization (17, 18, 38). In addition, the recruitment process is also mediated by other chemokines and its receptors, such as CXCL10, ICAM-1, VCAM, and CCR2 (33, 35, 39, 40). Although mice induced by BDL significantly increased mRNA and protein expression of CXCL10, ICAM-1, and VACM-1 in livers, this increase was obviously impacted by PlGF silencing (Figure 7).…”

“…In line with lower levels of intrahepatic macrophages, pro-inflammatory cytokines, such as TNF-α, IL-1β, and MCP-1 were significantly reduced in liver tissue by knockdown of PlGF by siRNA in BDL mice (Figures 6A,B). Several independent studies highlighted the importance of the chemokines receptor CCR2 and its main ligand, MCP-1, for monocyte/macrophage recruitment during experimental hepatic fibrosis, suggesting that inhibition of CCR2 or MCP-1 might bear therapeutic potential in chronic liver diseases (8, 9, 33, 41). In addition, macrophages also express multiple toll-like receptors (TLRs)—such as TLR4 and TLR9, and it has been reported that TLRs interact with oxDNA and microbial components, such as LPS, Hsp60, and other ligands, and result in macrophage activation and the productions of pro-inflammatory mediators (such as TNF-α and MCP-1) (32, 35, 42–44).…”

Immune-Mediated Repair: A Matter of Plasticity

“…Numerous mediators involved in the phenotype conversion of macrophages have been described, but so far their therapeutic potential remains uncertain in humans (86). For example, in vitro studies showed that GM-CSF could switch inflammatory monocytes to a reparative phenotype, leading to the idea that GM-CSF could exert beneficial effects on intestinal inflammation and wound healing associated with Crohn’s disease (87).…”

Impact of Pioglitazone on Macrophage Dynamics in Adipose Tissues of Cecal Ligation and Puncture-Treated Mice

“…However, they produce highly active mediators such as ROS that induce apoptosis and disrupt cell metabolism during the inflammatory process. 30) Taken together, our findings suggest that macrophages might contribute to inhibiting sepsis-triggered excessive inflammation of adipose tissue by reducing necrotic cell death numbers. These results suggest that macrophages infiltrated into visceral adipose tissues during CLP-induced sepsis may be associated with enhanced apoptosis and improved survival after CLP.…”