title: LILRA2 selectively modulates LPS-mediated cytokine production and inhibits phagocytosis by monocytes.
abstract: 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.
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Department of Pathology, University of New South Wales, Australia. [corrected].
authors.forename: Hao K
authors.initials: HK
authors.lastname: Lu
authors.forename: Ainslie
authors.initials: A
authors.lastname: Mitchell
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Endoh
authors.forename: Taline
authors.initials: T
authors.lastname: Hampartzoumian
authors.forename: Owen
authors.initials: O
authors.lastname: Huynh
authors.forename: Luis
authors.initials: L
authors.lastname: Borges
authors.forename: Carolyn
authors.initials: C
authors.lastname: Geczy
authors.forename: Katherine
authors.initials: K
authors.lastname: Bryant
authors.forename: Nicodemus
authors.initials: N
authors.lastname: Tedla
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; C105298:LILRA2 protein, human; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; C091196:opsonin receptor