MassIVE MSV000087357

Partial Public

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

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. [doi:10.25345/C5024Q] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Lair1 ; Colec12 ; phosphoproteomics ; Collagen

Contact

Principal Investigators:
(in alphabetical order)
Shannon Turley, Genentech, United States
Submitting User: hinklet
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