LIMP-2 links late phagosomal trafficking with the onset of the innate immune response to Listeria monocytogenes: a role in macrophage activation.
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.
Servicio de Inmunología, Hospital Santa Cruz de Liencres y Fundación Marqués de Valdecilla-Instituto de Formación e Investigación Marqués de Valdecilla, 39120 Liencres, Spain. deicme@humv.es
Eugenio
E
Carrasco-Marín
Lorena
L
Fernández-Prieto
Estela
E
Rodriguez-Del Rio
Fidel
F
Madrazo-Toca
Thomas
T
Reinheckel
Paul
P
Saftig
Carmen
C
Alvarez-Dominguez
D000818:Animals; D001692:Biological Transport / Q000276:immunology; D018955:CD36 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D007113:Immunity, Innate; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D051907:Lysosomal Membrane Proteins / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D010588:Phagosomes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; C489452:Scarb2 protein, mouse; D014409:Tumor Necrosis Factor-alpha