The scavenger receptor MARCO is a ligand for the immune inhibitory receptor LAIR-1 and regulates its function in cis
Akashdip Singh1,2, Saskia V Vijver1,2, Hajar Aglmous-Talibi1,2
1Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands.
Abstract:
LAIR-1 is an inhibitory receptor on immune cells that recognizes collagens and collagen domain-containing proteins. The high abundance of both LAIR-1 and its ligands suggests tight regulation of this interaction. MARCO is a scavenger receptor with a collagen-like domain that is highly expressed on immunosuppressive macrophages. Here, we identified MARCO as a ligand for LAIR-1. MARCO interacted with LAIR-1 in trans and induced inhibitory signaling by LAIR-1 in human natural killer (NK) cells. MARCO and LAIR-1 were coexpressed by human macrophages in tumors and after stimulation of monocyte-derived macrophages with the cytokine interleukin-10 (IL-10) in vitro. Single-molecule fluorescence microscopy demonstrated that MARCO and LAIR-1 interacted in cis on THP-1 macrophages. Whereas the interaction did not affect the scavenger function of MARCO on human macrophages, it reduced both LAIR-1 binding and the LAIR-1 signaling response to collagen. LAIR-1-mediated inhibitory function was increased after CRISPR-Cas9-mediated knockout of MARCO in IL-10-polarized primary human monocyte-derived macrophages. Our results identify MARCO as a regulator of LAIR-1 signaling and suggest that the induction of MARCO on immunosuppressive macrophages could enhance their function by releasing LAIR-1-mediated inhibition.
Insights
The scavenger receptor MARCO binds to the inhibitory receptor LAIR-1, modulating immune cell signaling. This interaction enhances immunosuppressive macrophage function by reducing LAIR-1 inhibition.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is an inhibitory receptor recognizing collagens.
- Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor highly expressed on immunosuppressive macrophages.
Purpose of the Study:
- To identify MARCO as a ligand for LAIR-1.
- To investigate the functional consequences of the MARCO-LAIR-1 interaction on immune cell signaling and macrophage function.
Main Methods:
- Co-immunoprecipitation assays to confirm MARCO-LAIR-1 interaction.
- In vitro assays using human natural killer (NK) cells and monocyte-derived macrophages.
- Single-molecule fluorescence microscopy to analyze MARCO-LAIR-1 cis interactions.
- CRISPR-Cas9 gene editing to knock out MARCO in macrophages.
Main Results:
- MARCO directly binds to LAIR-1, inducing inhibitory signaling in NK cells.
- MARCO and LAIR-1 are co-expressed on tumor-associated macrophages and IL-10-stimulated macrophages.
- MARCO-LAIR-1 interaction reduces LAIR-1 binding and signaling response to collagen.
- MARCO knockout enhances LAIR-1-mediated inhibition in IL-10-polarized macrophages.
Conclusions:
- MARCO acts as a novel regulator of LAIR-1 signaling.
- MARCO induction on immunosuppressive macrophages may enhance their function by alleviating LAIR-1-mediated inhibition.
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