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.

Proresolving Actions of Synthetic and Natural Protease Inhibitors Are Mediated by Annexin A1

“…Under a proinflammatory environment macrophages usually have proinflammatory phenotype (M1) that has little efferocytic capacity and increased capacity to engulf (phagocytose) foreign organisms. Inflammatory macrophages are skewed to the M2 phenotype in a resolution milieu and they produce IL-10 and TGF-b, which have anti-inflammatory actions (54,55). M2 macrophages are prone to efferocytose neutrophils (56), and uptake of apoptotic cells during the resolution of inflammation leads to their conversion to a proresolving CD11b low phenotype (27).…”

MFG-E8 and HMGB1 Are Involved in the Mechanism Underlying Alcohol-Induced Impairment of Macrophage Efferocytosis

“…Macrophage efferocytosis plays a critical role in the resolution of tissue injury and inflammation (6). It is a complex process that requires recognition of apoptotic cells by macrophages (40).…”

“…It triggers distinctive signal events in phagocytes and then induces cytoskeletal rearrangement as well as uptake of apoptotic cells. Rac1 and RhoA, two small Rho GTPases, have been demonstrated to play opposing roles in regulating engulfment of apoptotic cells: Rac1 enhances, while RhoA and Rho kinase (ROCK, a downstream effector of RhoA) inhibit the process (6).…”

“…Efferocytosis is a dynamic process which consists of recognition and engulfment of apoptotic cells by phagocytes (6). Recognition of dying cells is an early step of efferocytosis that is mediated by a group of bridging molecules and efferocytic receptors (7).…”

Enhancement of COPD biological networks using a web-based collaboration interface

“…The number of apoptotic cells was shown to increase in COPD because of exposure of lung tissue to toxic chemicals present in cigarette smoke; for example, and their accumulation was exacerbated by the simultaneous smoke-induced impairment of the phagocytic ability of alveolar macrophages 38 . Apoptotic cells exhibit surface changes that distinguish them from viable cells, and these changes were recognized by efferocytic receptors including CD36 molecule (CD36), CD14 molecule (CD14), and Stabilin-1/2 (STAB1:STAB2) 39 . Reduced efferocytosis observed in COPD because of oxidant-driven and Rho-mediated inactivation increased the likelihood of aberrant antigen exposure from apoptotic cells, thereby perpetuating the chronic inflammatory state that is a hallmark of COPD 40– 42 .…”