Homeostatic function of monocyte and interstitial lung macrophages are regulated via collagen binding domain receptor LAIR1 (scRNAseq)

Monocytes and macrophages play pivotal roles in tissue homeostasis and tumor progression. Here, we show that these cells express high levels of LAIR1, a known receptor for Collagen. Using a high throughput cell-based platform for interactome discovery, we identified Colec12, a protein expressed by stromal cells, as a novel high affinity LAIR1 ligand. Using a combination of genomic, phenotypic, global phosphoproteomics and transcriptomics assays, we corroborated the role of LAIR1 signaling in myeloid cells. Under homeostasis LAIR1 restrained proliferation and promoted survival of non-classical monocytes and dysregulation of this pathway led to an increase in classical monocytes and tissue-infiltrating macrophages in lungs. In tumors, LAIR1 deficiency in myeloid cells exacerbated metastasis to lungs and confirmed LAIR1 as a positive prognostic factor in human metastatic melanoma. Our study shows extracellular matrix provides monocytes and lung interstitial macrophages important homeostatic signals that are mediated via LAIR1. Methods: 10x single cell RNA sequencing was performed to characterize the differences between WT and LAIR1KO lung myeloid cells with and without tumor. Murine lungs were digested, cells were hashtagged and FACS-sorted for Interstitial macrophages, Alveolar macrophages, classical and nonclassical monocytes. Overall design: Examination of 3 hashtagged replicates from WT normal, LAIR1KO normal, B16/F10-bearing WT , and B16/F10-bearing LAIR1KO murine lungs