LIMP-2 links late phagosomal trafficking with the onset of the innate immune response to Listeria monocytogenes: a role in macrophage activation

• Published in: The Journal of biological chemistry Vol. 286; no. 5; pp. 3332 - 3341
• Main Authors: Carrasco-Marín, Eugenio, Fernández-Prieto, Lorena, Rodriguez-Del Rio, Estela, Madrazo-Toca, Fidel, Reinheckel, Thomas, Saftig, Paul, Alvarez-Dominguez, Carmen
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 04-02-2011
• Subjects: Animals; Biological Transport - immunology; CD36 Antigens - immunology; Cells, Cultured; Fibroblasts - cytology; Immunity, Innate; Immunology; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - immunology; Lysosomal Membrane Proteins - immunology; Macrophage Activation - immunology; Mice; Mice, Mutant Strains; Phagosomes - metabolism; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.146761

The innate immune response to Listeria monocytogenes depends on phagosomal bacterial degradation by macrophages. Here, we describe the role of LIMP-2, a lysosomal type III transmembrane glycoprotein and scavenger-like protein, in Listeria phagocytosis. LIMP-2-deficient mice display a macrophage-related defect in Listeria innate immunity. They produce less acute phase pro-inflammatory cytokines/chemokines, MCP-1, TNF-α, and IL-6 but normal levels of IL-12, IL-10, and IFN-γ and a 25-fold increase in susceptibility to Listeria infection. This macrophage defect results in a low listericidal potential, poor response to TNF-α activation signals, impaired phago-lysosome transformation into antigen-processing compartments, and uncontrolled LM cytosolic growth that fails to induce normal levels of acute phase pro-inflammatory cytokines. LIMP-2 transfection of CHO cells confirmed that LIMP-2 participates in the degradation of Listeria within phagosomes, controls the late endosomal/lysosomal fusion machinery, and is linked to the activation of Rab5a. Therefore, the role of LIMP-2 appears to be connected to the TNF-α-dependent and early activation of Listeria macrophages through internal signals linking the regulation of late trafficking events with the onset of the innate Listeria immune response.