The phagocytosis of microbial pathogens by cells of the innate immune system (such as macrophages) usually results in the induction of inflammatory responses, whereas the engulfment of apoptotic cells during tissue remodelling generally does not. A recent report in Science shows that activation of Toll-like receptor (TLR) signalling by bacteria, but not by apoptotic cells, underlies the distinct outcomes of these phagocytic pathways.

After uptake of bacteria by macrophages, phagosomes rapidly fuse with lysosomes (within 30 minutes) to become phagolysosomes, in which bacteria are degraded. To explore the role of TLR signalling in the regulation of this phagosome-maturation pathway, the authors followed the uptake of fluorescent bacteria by wild-type macrophages or those that lacked expression of TLR2 and TLR4, or MyD88 — a crucial TLR-signalling adaptor protein. They found that in the absence of TLRs or MyD88, internalization of bacteria (Escherichia coli, Staphylococcus aureus or Salmonella typhimurium) was delayed and degradation was less efficient, due to inefficient fusion of phagosomes with lysosomes. By contrast, phagocytosis of apoptotic cells was not affected in the absence of TLRs or MyD88, although the kinetics of phagocytosis of apoptotic cells was slower than the uptake of bacteria by wild-type macrophages — lysosome fusion only occurred after 1.5 to 2 hours. In fact, the rate of phagocytosis of apoptotic cells were similar to the rate of bacterial uptake by TLR-signalling-deficient cells. The authors therefore propose that two rates of phagosome maturation exist: a constitutive rate and a more rapid inducible rate, triggered by TLR signalling.

The authors went on to show that the rate of phagosome maturation depends on the ability of the specific phagosome cargo to trigger TLR signalling. In a single macrophage, bacteria and apoptotic cells are internalized into separate phagosomes; however, phagosomes containing apoptotic cells do not mature faster in macrophages that also have bacteria-containing phagosomes or in macrophages stimulated by the TLR4 ligand lipopolysaccharide, indicating that the inducible rate of maturation is phagosome autonomous.

Finally, using specific inhibitors, they show that the p38 mitogen-activated protein kinase that is activated downstream of TLRs is required for accelerated phagosome maturation triggered by bacteria. The authors suggest that the TLR–MyD88–p38 signalling pathway might be disrupted by some intracellular bacteria that avoid phagolysosomal fusion and the subsequent recognition by the innate and adaptive immune systems.