Mycobacterial lipoarabinomannan affects human polymorphonuclear and mononuclear phagocyte functions differently

Abstract

BACKGROUND AND OBJECTIVE: The role of mycobacterial lipoarabinomannan (LAM) in regulating the granulomatous response and its effects on cells involved in early responses to tuberculosis have not been clearly defined. The aim of this study was to acquire further evidence about the mechanisms by which LAM takes part in the host response to mycobacterial infections. DESIGN AND METHODS: We compared the in vitro ability of mannosylated LAM (ManLAM) and LAM lacking the terminal mannosyl units (AraLAM) to induce distinct responses in human polymorphonuclear (PMNs) and mononuclear phagocytes [both monocytes and 48-hr monocyte-derived macrophages (MDMs)]. The responses examined were chemotaxis, transient changes in free cytosolic calcium, phagocytosis and metabolic activation. RESULTS: AraLAM and ManLAM affected mononuclear, but not polymorphonuclear, phagocyte functions. Both forms of LAM were chemotactic for monocytes and MDMs. The LAM-induced chemotactic response required new protein synthesis, did not induce a rise in cytosolic free calcium levels and was partially inhibited (about 50%) by genistein, but not by calphostin C or PD 98059. Lastly, at physiologic doses ManLAM significantly reduced phagocytosis of M. tuberculosis and zymosan particles by MDMs. INTERPRETATION AND CONCLUSIONS: Different phagocytic cells can exhibit variable responses to AraLAM and ManLAM. Moreover, LAMs affect cell functions through different mechanisms. Protein synthesis and activation of protein tyrosine kinases are important intermediates in the signal transduction pathway of the chemotactic response of mononuclear phagocytes to AraLAM and ManLAM; whereas ManLAM-induced inhibition of macrophage phagocytic ability could depend on the binding of macrophage mannose receptors and/or the insertion of this molecule into cellular plasma membrane. Together these data highlight the danger of making generalizations regarding the activity of LAMs on immune defenses.