Macrophage polarization in tissue fibrosis

Abstract

Fibrosis can occur in all major organs with relentless progress, ultimately leading to organ failure and potentially death. Unfortunately, current clinical treatments cannot prevent or reverse tissue fibrosis. Thus, new and effective antifibrotic therapeutics are urgently needed. In recent years, a growing body of research shows that macrophages are involved in fibrosis. Macrophages are highly heterogeneous, polarizing into different phenotypes. Some studies have found that regulating macrophage polarization can inhibit the development of inflammation and cancer. However, the exact mechanism of macrophage polarization in different tissue fibrosis has not been fully elucidated. This review will discuss the major signaling pathways relevant to macrophage-driven fibrosis and profibrotic macrophage polarization, the role of macrophage polarization in fibrosis of lung, kidney, liver, skin, and heart, potential therapeutics targets, and investigational drugs currently in development, and hopefully, provide a useful review for the future treatment of fibrosis.

Keywords: Cardiac fibrosis; Kidney fibrosis; Liver fibrosis; Lung fibrosis; Macrophage polarization; Myofibroblasts; Skin fibrosis; Type 2 macrophage.

Figure 1. The major fibrosis-related signaling patnways.

Some signaling pathways are associated with tissue fibrosis, such as TGF-β/Smad, Wnt/β-Catenin, JAK/STAT3, and Notch which regulate target gene transcription, ECM production and transformation of different cells into myofibroblasts to lead to tissue fibrosis.

Figure 2. Macrophages in lung fibrosis.

After damage of alveolar epithelial cells, monocytes are activated by MCP-1 chemotaxis and further differentiated into M1 and M2 macrophages under the action of inflammatory factors. M1 macrophages secrete TNF-α, IL-6 and IL-23 to promote inflammation, and also produce MMP to degrade ECM. The secretion of TGF-β, IL-4, IL-13 and Wnt7 by M2 macrophages makes fibroblasts, endothelial cells and MSC transdifferentiate into myofibroblasts, producing ECM and leading to pulmonary fibrosis. Profibrotic TREM2CD206 and PLA2G7^high macrophage.

Figure 3. Macrophages in kindey fibrosis.

After kidney injury, locally released CCL2 recruits CCR2+/Ly6C^high monocyte/macrophages to the injured site, leading to local inflammatory response. Under the mediation of different signaling pathways macrophages are polarized to M1 and M2, which produce a variety of cytokines to maintain inflammation, activate fibroblasts, MMT, EMT and hypoxia-induced fibrosis.

Figure 4. Macrophages in liver fibrosis.

Kupffer cell is an inherent macrophage in hepatic sinusoids. When hepatocytes are damaged, inflammatory mediators such as chemokines are produced, and monocytes/macrophages are recruited into the tissues. The proliferation of myofibroblasts and the activation of resting HSC resulted in excessive deposition of ECM leading to liver fibrosis. A novel TERM2CD9 macrophage subsets promotes collagen formation by HSC and causes liver fibrosis. Moreover, monocytes/macrophages are also involved in fibrosis regression by secreting MMP9 or polarizing into M2b macrophages.

Figure 5. Macrophages in skin fibrosis.

M2 macrophages not only secrete cytokines such as IL-6 and TGF-β to promote the proliferation and migration of skin fibroblasts, but also produce PDGF and IGF to transform adipose cells into myofibroblasts, resulting in excessive deposition of collagen, and eventually leading to skin fibrosis.

Figure 6. Macrophages in cardiac fibrosis.

M1 macrophages produce inflammatory cytokines to promote inflammatory response, which can also be converted into M2 macrophages to participate in the process of fibrosis. M2 macrophages differentiate into myofibroblasts, activate cardiac fibroblasts and promote coronary endothelial cells to transform into myofibroblasts.