The scavenger receptor MARCO is a ligand for the immune inhibitory receptor LAIR-1 and regulates its function in cis
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.
Authors
- Michiel van der Vlist (ORCID: https://orcid.org/0000-0003-0931-8982)
- Akashdip Singh (ORCID: https://orcid.org/0000-0001-5326-8826)
- Jonathan Sitrin (ORCID: https://orcid.org/0009-0001-2496-5793)
- Suzanne Crawley (ORCID: https://orcid.org/0009-0007-6411-1294)
- Nebojsa Jukic (ORCID: https://orcid.org/0000-0002-7610-9729)
- Kristina A. Ganzinger (ORCID: https://orcid.org/0000-0001-9106-9406)
- Bin Fan (ORCID: https://orcid.org/0009-0005-3390-2654)
- Christian Niederauer (ORCID: https://orcid.org/0000-0002-4383-887X)
- Saskia V Vijver (ORCID: https://orcid.org/0000-0003-2526-3045)
- Daniel D. Kaplan (ORCID: https://orcid.org/0000-0001-8297-560X)
- Betty Li (ORCID: https://orcid.org/0009-0006-7293-9465)
- James Sissons (ORCID: https://orcid.org/0009-0000-9312-128X)
- Linde Meyaard (ORCID: https://orcid.org/0000-0003-0707-4793)
- Lee B. Rivera (ORCID: https://orcid.org/0000-0003-2658-1862)
- M Inês Pascoal Ramos (ORCID: https://orcid.org/0000-0003-3644-6517)
- Kalyani Mondal (ORCID: https://orcid.org/0009-0006-8415-4892)
- Peirong Chen
- Jing Zhou (ORCID: https://orcid.org/0000-0002-6611-7880)
- Zimple Matharu
- Hajar Aglmous-Talibi (ORCID: https://orcid.org/0009-0006-8254-730X)
Institutions
- Champalimaud Foundation (PT)
- Institute for Atomic and Molecular Physics (NL)
- University Medical Center Utrecht (NL)
- Oncode Institute (NL)
- NGM Biopharmaceuticals (United States) (US)
Publication Details
- Journal
- Science Signaling
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1126/scisignal.ado2768
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.80