Date Published: January 30, 2014
Publisher: Public Library of Science
Author(s): Somdeb BoseDasgupta, Jean Pieters, Sabine Ehrt.
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.
Macrophages are the main scavengers responsible for clearance of solutes and particulate material as well as to act as defense cells against invading microbes . 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 .
During inflammation, immune defense mechanisms must be upregulated to ensure a coordinated response towards the invaded infectious microbes. We here demonstrate that inflammatory stimuli reprogram the macrophage endocytic pathway from phagocytosis to macropinocytosis in a coronin 1-dependent manner. Reprogramming receptor-mediated phagocytosis to macropinocytosis allows macrophages to internalize cargo by bulk flow, rather then being restricted by specific receptor interactions; furthermore, internalizing material through macropinocytosis allows macrophages to efficiently target all incoming microbes to lysosomes for degradation. This may be especially important in the case of pathogens that can survive within non-activated macrophages by resisting phagosome-lysosome fusion, such as Mycobacterium spp. Also, although some bacteria can induce macropinocytic entry into non-phagocytes , most bacteria enter macrophages via phagocytosis and do not co-opt the macropinocytic pathway. Therefore, the ability of macrophages to switch from phagocytosis to macropinocytosis endows these cells with a mechanism to rapidly eliminate infectious material in lysosomes during an inflammatory challenge.