Apoptotic cells release adenine and

Apoptotic cells release adenine and uridine nucleotides through caspase-3/7-activated hexameric pannexin-1 channels on their surface (37). Extracellular nucleotides ATP and UTP act as find-me signals to promote cell clearance by stimulating recruitment of motile phagocytes expressing P2Y purinergic receptors and also by causing upregulation of phagocytic receptors (30, 38–40). Extracellular nucleotides can also exert immunomodulatory effects on macrophages via the breakdown of ATP into adenosine – a well known and potent modulator of macrophage inflammation (41, 42). Recent reports have shown that during efferocytosis, Gs-linked A2a and A2b adenosine receptors on macrophages mediate suppression of pro-inflammatory cytokines (e.g. CXCL1, CXCL2) and upregulation of pro-resolution factors (e.g. Nr4a1, Thbs1) (43, 44) (Figure 1). Interestingly, the precise mechanisms responsible for generating extracellular adenosine during efferocytosis are poorly understood. Although adenosine can be released directly from macrophages (43, 45), in many tissue settings the accumulation of extracellular adenosine is largely due to the hydrolysis of extracellular adenine nucleotides (i.e. ATP, ADP, AMP) by ecto-enzymes such as CD39 (ATP/ADP→AMP) and CD73 (AMP→adenosine) (41, 42). How these ecto-enzymes contribute to adenosine generation and immune modulation of macrophages during efferocytosis remains an open question.