Abstract
Following an infectious challenge, macrophages have to be activated in order to allow efficient clearance of infectious pathogens, but how macrophage activation is coupled to increased clearance remains largely unknown. We here describe that inflammatory stimuli induced the reprogramming of the macrophage endocytic machinery from receptor-mediated phagocytosis to macropinocytosis, allowing the rapid transfer of internalized cargo to lysosomes in a receptor-independent manner. Reprogramming occurred through protein kinase C-mediated phosphorylation of the macrophage protein coronin 1, thereby activating phosphoinositol (PI)-3-kinase activity necessary for macropinocytic uptake. Expression of a phosphomimetic form of coronin 1 was sufficient to induce PI3-kinase activation and macropinocytosis even in the absence of inflammatory stimuli. Together these results suggest a hitherto unknown mechanism to regulate the internalization and degradation of infectious material during inflammation.
Highlights
Macrophages are the main scavengers responsible for clearance of solutes and particulate material as well as to act as defense cells against invading microbes [1]
Macrophage activation by either interferon-c (IFN-c) or tumor necrosis factor-a results in the rapid delivery of the internalized mycobacteria to lysosomes followed by mycobacterial killing
Close inspection of the mycobacterial internalization process in activated macrophages by light microscopy showed that mycobacteria entered macrophages in large spacious vacuoles (Fig. 1A, arrows), which is an indication that the bacilli entered cells via macropinocytosis, rather than phagocytosis [14,26,27,28,29]
Summary
Macrophages are the main scavengers responsible for clearance of solutes and particulate material as well as to act as defense cells against invading microbes [1]. The main mechanisms via which macrophages can internalize and clear microbial material occurs through receptor-mediated phagocytosis. This process, making use of different cell surface receptors, including Fc receptors, complement receptors, scavenging receptors as well as several lectin receptors, ensure the uptake of particulate material into phagosomes followed by delivery of the cargo to lysosomes [1]. Pathogenic mycobacteria, which include the causative agent of tuberculosis, can be internalized via phagocytosis using different receptors, including complement receptor, scavenging receptors as well as lectin receptors such as the mannose receptor and DC-SIGN [2] [1]. The particular receptor involved may modulate the macrophage killing capacity by silencing certain macrophage responses such as the respiratory burst [12]
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