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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE171861 | GEO | 2021/04/12

REPOSITORIES: GEO

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Homeostatic functions of monocytes and monocyte-derived macrophages are regulated via collagen domain binding receptor LAIR1

Project description:Monocytes and monocyte-derived macrophages are myeloid cells that span all tissues and play pivotal roles in tissue homeostasis and tumor progression. Here, we show that these cells express high levels of leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), a known receptor for Collagen. We hypothesized that LAIR1 mediates the interaction between myeloid cells and the collagen-rich extracellular matrix (ECM). First, using a high throughput cell-based platform for membrane protein interactome discovery, we identified Colec12, a protein expressed by non-hematopoietic stromal cells, as a novel high affinity LAIR1 ligand. Global phosphoproteomics was employed to determine the signaling pathways triggered upon LAIR1 engagement by Colec12 and Collagen in monocytes, which suggested a main role in cell survival and cell cycle regulation. Using a combination of genomic, phenotypic and transcriptomics assays, we corroborated the homeostatic role of LAIR1 signaling in mice. Under homeostatic conditions, LAIR1 preferentially 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 in mice. Finally, we confirmed LAIR1 and LAIR1-expressing myeloid cell signatures as positive prognostic factors in human metastatic melanoma. Collectively, our study shows that ECM provides monocytes and monocyte-derived macrophages with important homeostatic signals that are mediated via the immunoreceptor LAIR1. This work illuminates new aspects of ECM-myeloid cell interactions that may be pertinent in cancer, fibrotic diseases and therapeutic development.

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

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LAIR1 prevents excess inflammatory tissue damage in S. aureus skin infection and Cutaneous T-cell Lymphoma [BMDM]

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LAIR1 prevents excess inflammatory tissue damage in S. aureus skin infection and Cutaneous T-cell Lymphoma [abscess]

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scRNA-seq analysis of lung CD64-expressing mononuclear cells, patrolling and classical monocytes from steady-state C57BL/6J mice

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