LILRA2 selectively modulates LPS-mediated cytokine production and inhibits phagocytosis by monocytes

• Published in: PloS one Vol. 7; no. 3; p. e33478
• Main Authors: Lu, Hao K, Mitchell, Ainslie, Endoh, Yasumi, Hampartzoumian, Taline, Huynh, Owen, Borges, Luis, Geczy, Carolyn, Bryant, Katherine, Tedla, Nicodemus
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.03.2012; Public Library of Science (PLoS)
• Subjects: Antigen presentation; Antigen presenting cells; Antigens; Bacteria; Beads; Biology; Blood & organ donations; Cell activation; Cell differentiation; Cells, Cultured; Coating effects; Crosslinking; Cytokines; Cytokines - biosynthesis; Dendritic cells; E coli; Eosinophils; Escherichia coli; Granulocyte colony-stimulating factor; Granulocyte-macrophage colony-stimulating factor; Humans; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin G - immunology; Immunoglobulin G - metabolism; Infections; Inflammation; Innate immunity; Interferon; Interleukin 10; Interleukin 12; Interleukin 6; Interleukin 8; Killer cells; Kinases; Leishmania; Leprosy; Leukocytes (basophilic); Leukocytes (eosinophilic); Leukocytes (neutrophilic); Leukocytes - metabolism; LILRA2 protein; Lipopolysaccharides; Lipopolysaccharides - immunology; Lymphocytes; Macrophages; Medicine; Monocyte chemoattractant protein 1; Monocytes; Monocytes - immunology; Monocytes - metabolism; mRNA; Natural killer cells; Nitric oxide; Opsonization; Pathology; Phagocytosis; Phagocytosis - immunology; Protein Binding - immunology; Proteins; Receptors; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; RNA; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033478

The activating immunoglobulin-like receptor, subfamily A, member 2 (LILRA2) is primarily expressed on the surface of cells of the innate immunity including monocytes, macrophages, neutrophils, basophils and eosinophils but not on lymphocytes and NK cells. LILRA2 cross-linking on monocytes induces pro-inflammatory cytokines while inhibiting dendritic cell differentiation and antigen presentation. A similar activating receptor, LILRA4, has been shown to modulate functions of TLR7/9 in dendritic cells. These suggest a selective immune regulatory role for LILRAs during innate immune responses. However, whether LILRA2 has functions distinct from other receptors of the innate immunity including Toll-like receptor (TLR) 4 and FcγRI remains unknown. Moreover, the effects of LILRA2 on TLR4 and FcγRI-mediated monocyte functions are not elucidated. Here, we show activation of monocytes via LILRA2 cross-linking selectively increased GM-CSF production but failed to induce IL-12 and MCP-1 production that were strongly up-regulated by LPS, suggesting functions distinct from TLR4. Interestingly, LILRA2 cross-linking on monocytes induced similar amounts of IL-6, IL-8, G-CSF and MIP-1α but lower levels of TNFα, IL-1β, IL-10 and IFNγ compared to those stimulated with LPS. Furthermore, cross-linking of LILRA2 on monocytes significantly decreased phagocytosis of IgG-coated micro-beads and serum opsonized Escherichia coli but had limited effect on phagocytosis of non-opsonized bacteria. Simultaneous co-stimulation of monocytes through LILRA2 and LPS or sequential activation of monocytes through LILRA2 followed by LPS led lower levels of TNFα, IL-1β and IL-12 production compared to LPS alone, but had additive effect on levels of IL-10 and IFNγ but not on IL-6. Interestingly, LILRA2 cross-linking on monocytes caused significant inhibition of TLR4 mRNA and protein, suggesting LILRA2-mediated suppression of LPS responses might be partly via regulation of this receptor. Taken together, we provide evidence that LILRA2-mediated activation of monocytes is significantly different to LPS and that LILRA2 selectively modulates LPS-mediated monocyte activation and FcγRI-dependent phagocytosis.