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Signal."],"published-print":{"date-parts":[[2025,12,9]]},"abstract":"<jats:p>LAIR-1 is an inhibitory receptor on immune cells that recognizes collagens and collagen domain\u2013containing 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\u2013mediated inhibitory function was increased after CRISPR-Cas9\u2013mediated knockout of MARCO in IL-10\u2013polarized 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\u2013mediated inhibition.<\/jats:p>","DOI":"10.1126\/scisignal.ado2768","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T18:58:45Z","timestamp":1765306725000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["The scavenger receptor MARCO is a ligand for the immune inhibitory receptor LAIR-1 and regulates its function in cis"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5326-8826","authenticated-orcid":true,"given":"Akashdip","family":"Singh","sequence":"first","affiliation":[{"name":"Centre for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, Netherlands."},{"name":"Oncode Institute, Utrecht, 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