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

ABSTRACT: Background: We observed that LAIR1 is highly expressed in murine nonclassical monocytes. This study aims to understand gene expression differences between LAIR1-/- and LAIR1+/+ murine bone marrow nonclassical monocytes. Methods: Ly6C- nonclassical monocytes were sorted out of murine bone marrows and harvested for RNA-seq.

ORGANISM(S): Mus musculus

PROVIDER: GSE171862 | GEO | 2021/04/12

REPOSITORIES: GEO

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

Project description: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.

2021-04-12 | GSE171861 | GEO

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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Blocking LAIR1 signaling in immune cells inhibits tumor development

Project description:LAIR1 is an inhibitory immune cell receptor. We used single cell RNA sequencing (scRNA-seq) to analyze the immune cell distribution in the implanted B16 tumor tissues of Vav-cre human LAIR1 transgenic and LAIR1-/- C57bl/6j mice after control or anti-LAIR1 blocking antibody treatment.

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

Project description:Patients with cutaneous T cell lymphoma (CTCL) experience high morbidity and mortality due to S. aureus skin infections and sepsis, but the causative immune defect is unclear. We propose that high levels of LAIR2 in CTCL suppress LAIR1 inhibitory signaling, promoting inflammation and tissue damage, which increases S. aureus susceptibility. Mice do not have a LAIR2 homolog, so we used Lair1 KO mice to model LAIR2 overexpression. In a model of subcutaneous S. aureus skin infection, Lair1 KO mice had significantly larger abscesses and areas of dermonecrosis compared to WT. Lair1 KO exhibited a pattern of increased inflammatory responses in infection and sterile immune stimulation, including increased production of proinflammatory cytokines and myeloid chemokines, neutrophil ROS, and collagen/ECM remodeling pathways. Notably, compared to WT, Lair1 KO infected skin had a similar bacterial burden and neutrophils and monocytes had equivalent S. aureus phagocytosis. These findings support a model in which lack of LAIR1 signaling results in an excessive inflammatory response that does not improve infection control. CTCL tissues harbored similar patterns of increased cytokine and collagen production, suggesting that high levels of LAIR2 in CTCL recapitulates Lair1 KO, causing inflammatory tissue damage and compromising host defense against S. aureus infection.

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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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Genomic characterization of murine monocytes reveals C/EBPb dependence of Ly6C-cells [ChIP data]

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Project description:Administration of G-CSF mobilizes a unique population of CD11b+Ly6C+CD34+mature monocytes that can inhibit GVHD in murine models of BMT via an iNOS-dependent mechanism. The transcriptional profiles of flow sorted lineage-CD11b+CD34+ cells from G-CSF treated mice were compared with conventional splenic Ly6C+ and Ly6C- monocytes, progenitor cells and cultured myeloid-derived suppressor cells. Further comparisons were made with lineage-CD11b+CD34+ cells from G-CSF treated mice that had been grown in culture or that were derived from iNOS ko mice. We used microarrays to detail the global programme of gene expression underlying diffrenetiation of each of these cell types Lin-CD11b+CD34+ populations were isolated directly from the spleens of G-CSF-treated C57BL/6 mice or iNOS ko mice. In untreated C57BL/6 mice, Lin-CD11b+CD115+Ly6C+ and Lin-CD11b+CD115+Ly6C- monocytes were isolated from the spleen and Lin-CD117+CD115+CD135-Ly6C+CD11b- common monocyte progenitors were isolated from the bone marrow. Myeloid-derived suppressor cells (Ly6C+CD11b+ cells derived from G-CSF, GM-CSF and IL-13 cultured C57BL/6 bone marrow) were also isolated and compared with the above populations. Lin-CD11b+CD34+ spleen cells derived from G-CSF-treated C57BL/6 mice were cultured for 3 days in Flt3 ligand and SCF and then compared to the original input population.

2015-04-01 | E-GEOD-65670 | biostudies-arrayexpress

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

Project description:Homeostatic function of monocyte and interstitial lung macrophages are regulated via collagen binding domain receptor LAIR1.

| PRJNA721204 | ENA

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

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

| PRJNA721211 | ENA

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

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

| PRJNA721210 | ENA

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