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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE269178 | GEO | 2024/07/31

REPOSITORIES: GEO

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

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.

2024-07-31 | GSE269177 | GEO

Anti-tumor activity of a novelLAIR1antagonist in combination with anti-PD-1to treat collagen-rich solid tumors (GeoMx)

Project description:We recently reported that resistance to PD-1-blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1), and thus we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. Here, we report LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist monoclonal antibody, elicits myeloid inflammation and allogeneic T cell responses by binding to LAIR1 and blocking collagen engagement. Further, a mouse-reactive NGM438 surrogate antibody sensitized refractory KP mouse lung tumors to anti-PD-1 therapy and resulted in increased intratumoral CD8+ T cell content and inflammatory gene expression. These data place LAIR1 at the intersection of stroma and suppressive myeloid cells and support the notion that blockade of the LAIR1/collagen axis can potentially address resistance to checkpoint inhibitor therapy in the clinic.

2024-03-04 | GSE260598 | GEO

Anti-tumor activity of a novelLAIR1antagonist in combination with anti-PD-1to treat collagen-rich solid tumors (human)

2024-03-04 | GSE260597 | GEO

Anti-tumor activity of a novelLAIR1antagonist in combination with anti-PD-1to treat collagen-rich solid tumors (mouse)

2024-03-04 | GSE260596 | GEO

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

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

| PRJNA1120460 | ENA

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

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

| PRJNA1120461 | ENA

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

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.

2022-10-27 | GSE212516 | 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.

2021-05-03 | MSV000087357 | MassIVE

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

Project description: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.

2021-04-12 | GSE171862 | GEO

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