Infiltrating monocytes in liver injury and repair

Abstract

Noninfectious liver injury causes many acute and chronic liver diseases around the globe, and particularly in developed nations. Bone marrow-derived monocytes infiltrate the damaged liver tissue and are a critical component of the innate immune response that may drive injury resolution or host death in the short term or chronic inflammation, fibrosis and hepatocellular carcinoma in the long term. Monocytes often play dual roles in liver injury-both perpetuating inflammation and promoting resolution of inflammation and fibrosis. Thus, we will address the role that monocytes play in different experimental forms of noninfectious liver injury; considering in particular the importance of the transition from inflammatory Ly6C^hi monocytes to pro-resolution Ly6C^lo monocyte-derived macrophages and the consequences of this transition for disease progression and resolution.

Figure 1

The differentiation of Ly6C^hi monocytes in liver injury. Following liver injury, monocytes traffic to the tissue. In the liver, Ly6C^hi monocytes (blue arrow) are recruited by CCL2- and CCR2-dependent mechanisms and extravasate from the circulation into the tissue where they surround the site of injury. The Ly6C^hiCCR2⁺CX₃CR1^lo monocyte-derived macrophages then differentiate into Ly6C^loCCR2⁻CX₃CR1^hi monocyte-derived macrophages. This transition relies on a number of mechanisms and interactions (blue to green arrow) including phagocytosis, IL-10 and IL-4, and CX₃CR1. The CCR8, CSF1R and stabilin-1 receptors and the transcription factor Nur77 may also play a role in this process. Infiltrating Ly6C^hi monocytes and the Ly6C^hi monocyte-derived macrophages are inflammatory and contribute to inflammation and the progression of fibrosis, whereas Ly6C^lo monocytes and monocyte-derived macrophages exhibit tissue repair and restorative phenotypes, leading to the resolution of fibrosis. Alternate pathways observed in other tissues that may also occur in the liver (gray arrows) are the extravasation of the Ly6C^lo monocyte subset into the injured tissue within 1–2 h following injury, and successive recruitment of Ly6C^hi and Ly6C^lo monocytes that then differentiate into their respective inflammatory and pro-resolution macrophage populations.