Abstract
Swift and continuous phagocytosis of apoptotic cells can be achieved by modulation of calcium flux in phagocytes. However, the molecular mechanism by which apoptotic cells modulate calcium flux in phagocytes is incompletely understood. Here, using biophysical, biochemical, pharmaceutical, and genetic approaches, we show that apoptotic cells induced the Orai1-STIM1 interaction, leading to store-operated calcium entry (SOCE) in phagocytes through the Mertk-phospholipase C (PLC) γ1-inositol 1,4,5-triphosphate receptor (IP3R) axis. Apoptotic cells induced calcium release from the endoplasmic reticulum, which led to the Orai1-STIM1 association and, consequently, SOCE in phagocytes. This association was attenuated by masking phosphatidylserine. In addition, the depletion of Mertk, which indirectly senses phosphatidylserine on apoptotic cells, reduced the phosphorylation levels of PLCγ1 and IP3R, resulting in attenuation of the Orai1-STIM1 interaction and inefficient SOCE upon apoptotic cell stimulation. Taken together, our observations uncover the mechanism of how phagocytes engulfing apoptotic cells elevate the calcium level.
Highlights
Efferocytosis is a process that removes apoptotic cells generated throughout life in multicellular organisms and is essential for homeostasis and during development [1]
Calcium is necessary for binding of PS to its receptors [27,28,29]; it is possible that extracellular calcium is crucial for recognition and engulfment of apoptotic cells by phagocytes
Phagocytosis of apoptotic cells by bone marrow-derived macrophages (BMDMs) treated with EGTA or incubated in calcium-free medium was drastically diminished (Figure 1A), which was likely because apoptotic cells did not bind to them well (Figure 1B,C)
Summary
Efferocytosis is a process that removes apoptotic cells generated throughout life in multicellular organisms and is essential for homeostasis and during development [1]. The TAM receptors, Tyro, Axl, and Mertk, comprise a unique family of receptor tyrosine kinases (RTKs). This family regulates various cellular processes, including cell proliferation, adhesion, migration, and efferocytosis [10]. Apoptotic cell stimulation induces phosphorylation of Mertk and phospholipase C (PLC) γ2 and the association of these two proteins. These suggest that Mertk can transduce signals via its kinase domain and PLCγ2 during efferocytosis [16]. Signal transduction downstream of Mertk during efferocytosis is incompletely understood
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