The role of macrophages in the resolution of inflammation

Abstract

Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue. Macrophage function is a sum of their ontogeny, the local environment in which they reside, and the type of injuries or pathogen to which they are exposed. In this Review, we discuss the role of macrophages in the restoration of tissue function after injury, highlighting important questions about how they respond to and modify the local microenvironment to restore homeostasis.

Figure 1. Tissue-resident macrophages and monocyte-derived macrophages play distinct roles in tissue injury and repair.

Tissue-resident macrophages (TRMs) originate from the yolk sac and fetal liver during development and persist in many tissues via self-renewal. During homeostasis (left panel), TRMs clear apoptotic cells, proteins, and phospholipids and either clear or respond to toxins, particulates, and pathogens within the local microenvironment. Many TRMs are capable of maintaining themselves by local proliferation without the contribution of monocyte-derived macrophages (MoMs). TRMs produce a variety of factors that stimulate the activation, proliferation, and differentiation of immune cells, epithelial cells, endothelial cells, fibroblasts, and stem cells that facilitate tissue homeostasis. In response to tissue injury (middle panel), bone marrow–derived monocytes are recruited to the injured tissue, where they differentiate into MoMs. During injury, TRMs and MoMs play distinct roles; usually MoMs exhibit a more robust inflammatory response. During the resolution of injury (right panel), TRMs may die or expand through self-renewal and repopulate the niche. MoMs either undergo apoptosis or persist, sometimes gaining the capacity for self-renewal. Over time, the phenotypes of TRMs and MoMs become increasingly similar. Arrows indicate interactions with other cell types.

Figure 2. Role and kinetics of macrophages during tissue injury and repair.

(A) Monocytes are recruited to the tissue during injury, where they differentiate into macrophages in response to cues provided by the injured microenvironment. We propose two models to understand the distinct roles of monocytes in promoting tissue injury and tissue repair during injury resolution, which are not mutually exclusive. In the passive repair model (top panel), tissue regeneration restores signals that promote macrophage differentiation into cells that increasingly resemble tissue-resident macrophages. As the homeostatic function of macrophages is restored, tissue repair is accelerated, creating a feed-forward loop that restores homeostasis. In the active repair model (bottom panel), monocyte-derived macrophages respond to cues in their microenvironment and express or secrete factors that drive tissue repair. Interactions include the uptake of apoptotic cells (often neutrophils), regulatory T cells, pathogens, and epithelial cells. These monocyte-derived macrophages might promote the resolution of inflammation through secretion of antiinflammatory and pro-repair mediators including metabolic intermediates, pro-resolution lipid mediators, antiinflammatory cytokines, and matrix remodeling proteins. (B) The kinetics of monocyte-derived macrophage recruitment to tissues is a subject of active investigation. A single wave of monocytes may enter during injury and be progressively reshaped into pro-resolving macrophages in response to cues within the local microenvironment (top panel). Alternatively, distinct waves of monocyte-derived macrophages might be involved in tissue injury (red) and tissue repair (purple) (middle panel), or monocytes with varying functions might be continuously recruited over the course of tissue injury and repair (bottom panel).

Figure 3. Major questions remaining regarding the role of macrophages in tissue injury and repair.