Editors' ChoiceInnate Immunity

Macrophages don’t take more than they can eat

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Science Signaling  20 Jun 2017:
Vol. 10, Issue 484, eaao1183
DOI: 10.1126/scisignal.aao1183

Innate immune signaling feeds forward to control the rate at which macrophages phagocytose bacteria.

Macrophages protect the body from infection by internalizing extracellular bacteria in phagosomes that fuse first with endosomes and then with acidic lysosomes, where the bacterial cargo is degraded. The proper concentration of anions in endosomes is required for these organelles to accumulate Ca2+, which is subsequently released to drive endosome-lysosome fusion (see also Monahan and Silverman). Wong et al. found that the Drosophila melanogaster Cl channel ClC-b, which is homologous to the mammalian late endosomal and lysosomal Cl transporter CLCN7, was required specifically in macrophages for the clearance of nonpathogenic bacteria that had been injected into the fly body cavity. Macrophages lacking ClC-b internalized bacteria, but they degraded the bacteria more slowly than did macrophages from wild-type flies. The endolysosomal cation channel TRMPL, which is required for the release of Ca2+ from endosomes, was also required for proper bacterial clearance. ClC-b, and the lysosomal degradation of bacteria were required for the activation of Relish, the Drosophila homolog of nuclear factor κB (NF-κB), in the macrophage cytosol by the pattern recognition receptor PGRP-LE. Although overexpression of ClC-b did not overcome the reduction in bacterial clearance caused by knocking down Relish, activation of PGRP-LE did, indicating that activation of Relish promotes the internalization and degradation of bacteria. These findings suggest that flux through the lysosomal pathway, which generates the ligands that activate pattern recognition receptors and NF-κB, is required for the continued phagocytosis of bacteria. Experiments in cultured mouse RAW264.7 cells (a macrophage cell line) demonstrated that this mechanism is likely conserved. Coupling of the rate of phagocytosis to lysosomal flux might ensure that macrophages do not take up more bacteria than they can degrade.

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