Apoptotic Cells Induce Migration of Phagocytes via Caspase-3-Mediated Release of a Lipid Attraction Signal

Abstract

Efficient engulfment of the intact cell corpse is a critical end point of apoptosis, required to prevent secondary necrosis and inflammation. The presentation of "eat-me" signals on the dying cell is an important part of this process of recognition and engulfment by professional phagocytes. Here, we present evidence that apoptotic cells secrete chemotactic factor(s) that stimulate the attraction of monocytic cells and primary macrophages. The activation of caspase-3 in the apoptotic cell was found to be required for the release of this chemotactic factor(s). The putative chemoattractant was identified as the phospholipid, lysophosphatidylcholine. Further analysis showed that lysophosphatidylcholine was released from apoptotic cells due to the caspase-3 mediated activation of the calcium-independent phospholipase A(2). These data suggest that in addition to eat-me signals, apoptotic cells display attraction signals to ensure the efficient removal of apoptotic cells and prevent postapoptotic necrosis.

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…One of the first identified recruitment signals for apoptotic cell engulfment was lysophosphatidylcholine (LPC). 23 Lauber et. al.…”

“…al. 23 showed that the cell supernatants taken from apoptotic MCF7 cells could induce phagocyte migration. The authors linked soluble LPC as the factor responsible for recruitment.…”

“…24 This release of LPC was not simply leakage of cellular contents as the membrane integrity was intact. LPC release was dependent on caspase-3-mediated activation of calcium-independent phospholipase A2, 23 which hydrolizes membrane-lipid phosphatidylcholine. However, it is not known whether LPC generation during apoptosis occurs intracellularly, extracellularly, or both, as the perturbed membrane structure is susceptible to secretory phospholipase A2 activity.…”

MCF-7 breast carcinoma cells do not express caspase-3

“…For instance, whereas the caspase-3-mediated cleavages of a-fodrin, gelsolin, rho-associated kinase-1 (ROCK-1) and p21-activated kinase 2 (PAK2) contribute to membrane blebbing, cleavage of the inhibitor of the caspase-activated DNase (ICAD) leads to the typical DNA fragmentation pattern observed in apoptosis [1]. Furthermore, with the cleavagemediated activation of the calcium-independent phospholipase A2 and subsequent production of the chemotactic phospholipid lysophosphatidylcholine, caspase-3 appears to be also responsible for the generation of so-called ''eatme'' signals that induce migration of phagocytes to the site of apoptotic cell death [6]. Thus, caspase-3 not only instigates and pursues the demise of a cell, but, in addition, makes sure that the corpse is properly disposed, a function crucial for avoiding inflammatory processes.…”

PS externalization: from corpse clearance to drug delivery

“…From a more general point of view, phospholipids (and, in particular, their oxidatively modified counterparts) appear to have assumed several key roles in apoptosis, at least in mammalian cells, including the cardiolipin-dependent release of proapoptotic factors from mitochondria, 34 and the lysophosphatidylcholine-triggered chemoattraction of macrophages to sites of apoptotic lesions. 35 Further studies in the field of oxidative lipidomics of apoptosis are expected to shed more light on the manifold roles of these ubiquitous cellular signaling molecules.…”