Modulation of macrophage efferocytosis in inflammation

Abstract

A critical function of macrophages within the inflammatory milieu is the removal of dying cells by a specialized phagocytic process called efferocytosis ("to carry to the grave"). Through specific receptor engagement and induction of downstream signaling, efferocytosing macrophages promote resolution of inflammation by (i) efficiently engulfing dying cells, thus avoiding cellular disruption and release of inflammatory contents, and (ii) producing anti-inflammatory mediators such as IL-10 and TGF-β that dampen pro-inflammatory responses. Evidence suggests that plasticity in macrophage programming, in response to changing environmental cues, modulates efferocytic capability. Essential to programming for enhanced efferocytosis is activation of the nuclear receptors PPARγ, PPARδ, LXR, and possibly RXRα. Additionally, a number of signals in the inflammatory milieu, including those from dying cells themselves, can influence efferocytic efficacy either by acting as immediate inhibitors/enhancers or by altering macrophage programming for longer-term effects. Importantly, sustained inflammatory programming of macrophages can lead to defective apoptotic cell clearance and is associated with development of autoimmunity and other chronic inflammatory disorders. This review summarizes the current knowledge of the multiple factors that modulate macrophage efferocytic ability and highlights emerging therapeutic targets with significant potential for limiting chronic inflammation.

Keywords: alternative activation; apoptotic cell; classical activation; efferocytosis; inflammation; macrophage.

Figure 1

Macrophage programming either in vitro or in vivo determines efferocytic capacity. Left: Inflammatory macrophages, e.g., generated by stimuli such as LPS + IFNγ have heightened bactericidal activity and production of pro-inflammatory mediators, and are programmed poorly for efferocytosis. Right: Following activation of the nuclear receptors, pro-resolving, or resolution-phase macrophages are programmed for heightened efferocytosis, with increased expression of receptors and bridge molecules required for the recognition of apoptotic cells, and the production of anti-inflammatory cytokines. In vivo, over the course of acute inflammation macrophage programming and function transitions from that of inflammatory macrophages to resolution-phase macrophages.

Figure 2

Early acting inhibitors and enhancers influence efferocytic capacity of macrophages. Rho/Rac balance is altered by inhibitors (left) and enhancers (right). ROS, reactive oxygen species; AnxV, annexin A5; other abbreviations are defined in the text. It is likely that early acting agents also contribute to longer-term macrophage programming as illustrated in Figure 1.