Differential regulation of macrophage galactose-type lectin (MGL) orthologs by mycobacterial ligands

Abstract

Abstract Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is responsible for approximately 10 million new infections and 1.5 million deaths each year. Pattern recognition receptors (PRRs) expressed on the surface of macrophages play an important role in orchestrating the immune response to pathogens. Amongst these, the C-type lectin receptors (CLRs) are an important PRR system that is increasingly understood to mediate innate immunity to mycobacteria. We recently described a new anti-bacterial and anti-inflammatory role for the macrophage galactose-type lectin-1 (MGL-1) in a murine model of experimental TB. MGL is a type II CLR that is known to recognize galactose and N-acetylgalactosamine monosaccharides. We observed that exposure to Mtb activated expression of both murine MGL orthologues, MGL-1 and MGL-2. The specific pathogen-associated molecular patterns that activate MGL orthologue transcription, however, have yet to be determined. Here we demonstrate that expression of MGL-1 and MGL-2 are differentially regulated by cytokines, TLR agonists, and mycobacterial ligands. MGL-1 expression is activated by dexamethasone, IL-4, IL-10, and the mycobacterial cell wall glycolipid Trehalose 6,6′-dimycolate. In contrast, MGL-2 expression is activated by TLR2/6 and TLR2/1 agonists and total lipid extracts of mycobacteria. Use of a MyD88 inhibitor further showed that molecular regulation of MGL-1 and MGL-2 transcription, following exposure of macrophages to mycobacteria, is TLR pathway-dependent. These results identify overlapping and unique host immune pathways that differentially activate MGL orthologues following exposure to Mtb and could be targeted through immune modulation.