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Diabetes exacerbates destructive inflammation by activating the CD137L-CD137 axis in dendritic and gd T-cells

ABSTRACT: Periodontal disease, a bacterial infection affecting a large percentage of the world's population, is an important risk factor for several systemic diseases and is significantly worsened by diabetes. To investigate how diabetes exacerbates the inflammatory response to bacteria in this disease, we combined insights from murine and human studies. Through single-cell RNA sequencing, we identified a compelling hyperglycemia-driven molecular pathway: the upregulation of CD137L in dendritic cells and increased expression of its receptor, CD137, in γδ T-cells. The CD137L-CD137 axis emerged as a pivotal mediator of diabetes-induced inflammatory tissue destruction. Antibody-mediated inhibition of CD137L markedly reduced the diabetes-driven bone loss, neutrophil recruitment, expansion of γδ T-cells, and excessive infiltration by IL17A+ cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE295144 | GEO | 2025/11/20

REPOSITORIES: GEO

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Diabetes exacerbates destructive inflammation by activating the CD137L-CD137 axis in dendritic and gd T-cells

Project description:Diabetes exacerbates destructive inflammation by activating the CD137L-CD137 axis in dendritic and gd T-cells

| PRJNA1253614 | ENA

Transcriptional and functional characterization of dendritic cell differentiation induced by CD137 ligand reverse signaling in human monocytes

Project description:The contribution of monocyte-derived dendritic cells (DC) to an immune response is essential for the elimination of pathogens. In vitro DC can be generated by treatment of monocytes with GM-CSF + IL-4 but it is unknown what stimuli induce the differentiation of monocytes to DC in vivo. CD137L-DC are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. Since CD137 is only expressed at sites of inflammation it would be a suitable signal for the induction of monocyte-derived DC. Here we report on gene expression analysis of CD137L-DC, immature and mature classical DC, monocytes and macrophages which indicates that CD137L-DC have a gene signature that is most similar to that of classical DC. Additionally, CD137L-DC signature genes are highly enriched in monocyte-derived DC which were isolated from sites of inflammation. Also cell surface marker expression and cytokine secretion of CD137L-DC are highly similar to that of inflammatory monocyte-derived DC. CD137L-DC express high levels of adhesion molecules, display strong attachment and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study identifies a physiological stimulus for the generation of monocyte-derived DC in vivo. A total of 30 expression profiles were obtained, on 6 APC subtypes from 5 different donors

2016-06-30 | E-GEOD-60199 | biostudies-arrayexpress

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

Project description:CD137 (4-1BB) is a member of the TNFR family that mediates potent T-cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies. CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137-signaling complex. Moreover, cIAPs are required for CD137 signaling towards the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC-mimetics that trigger cIAPs degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models and cIAPs are also required for signaling from CARs encompassing CD137’s cytoplasmic tail.

2024-05-24 | PXD042585 | Pride

Transcriptional and functional characterization of dendritic cell differentiation induced by CD137 ligand reverse signaling in human monocytes

2016-06-30 | GSE60199 | GEO

CD137 promotes bone metastasis of breast cancer by enhancing the migration and osteoclast differentiation of monocytes/macrophages

Project description:Rationale: Bone is the most common metastatic site of breast cancer. CD137(4-1BB), a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed in activated leukocytes. Previous study demonstrates the effect of CD137-CD137L bidirectional signaling pathway on RANKL-mediated osteoclastogenesis. However, the role of CD137 in bone metastasis of breast cancer needs further study. Methods: Stable monocyte/macrophage cell lines with Cd137 overexpression and silencing were established. Western blot, real-time PCR, transwell and tartrate-resistant acid phosphatase staining were used to detect the regulatory effect of CD137 on migration and osteoclastogenesis of monocytes/macrophages in vitro. Spontaneous bone metastasis mouse model was established, bioluminescent images, immunohistochemistry and histology assay were performed to detect the function of CD137 in bone metastasis in vivo. Results: We found that CD137 promotes the migration of monocytes/macrophages to tumor microenvironment by upregulating the expression of Fra1. It also promoted the differentiation of monocytes/macrophages into osteoclasts at the same time, thus providing a favorable microenvironment for the colonization and growth of breast cancer cells in bone. Based on these findings, a novel F4/80-targeted liposomal nanoparticle encapsulating the anti-CD137 Ab blocking antibody (NP-aCD137 Ab-F4/80) was synthesized. This nanoparticle could inhibit both bone and lung metastases of 4T1 breast cancer cells with high efficacy in vivo. In addition, it increased the therapeutic efficacy of Fra1 inhibitor on tumor metastasis. Conclusions: Taken together, these findings reveal the promotion effect of macrophage/monocyte CD137 on bone metastases and provide a promising therapeutic strategy for metastasis of breast cancer.

2019-06-20 | GSE130013 | GEO

CD137 (4-1BB) ligand mediates CD4 T-cell immuno-surveillance of pre- lymphoma B cells in a lymphoma-prone mouse model

Project description:Aberrant expression of the proto-oncogene BCL6 is a driver of tumorigenesis in diffuse large B cell lymphoma (DLBCL). Mice overexpressing BCL6 from the B cell-specific immunoglobulin heavy chain μ intron promoter (Iμ-Bcl6 Tg/+ ) develop B cell lymphomas with features typical of human DLBCL. B cell lymphoma development in these mice is tightly controlled by T cells; however, the mechanisms of this immune surveillance are poorly understood. Here we show that CD4 T cells contribute to the control of lymphoproliferative disease in lymphoma-prone Iμ-Bcl6 Tg/+ mice. Furthermore, we reveal that this CD4 T-cell immuno-surveillance requires signaling by the co-stimulatory molecule, CD137 ligand (CD137L; also known as 4-1BBL), which promotes the transition of pre malignant B cells with an activated phenotype into the germinal center stage, preventing their hazardous accumulation. Thus, CD137L-mediated CD4 T cell immuno-surveillance adds another layer of protection against B-cell malignancy to that provided by CD8 T-cell cytotoxicity.

2023-01-04 | GSE196100 | GEO

CD137-CIS IO

Project description:CD137 cis-costimulation is superior to trans-costimulation at inducing transcriptomic differences in T-cell proliferation and DNA repair programs We used microarrays to detail differentially expressed genes of cis- and trans CD137-costimulated CD8 T cells with respect to CD3-TCR stimulation

2021-09-28 | GSE158041 | GEO

CD137-CIS IO

Project description:CD137-CIS IO

| PRJNA663842 | ENA

Effect of CD137 (4-1BB) triggering on human monocytes

Project description:The cell surface glycoprotein CD137, which is also known as 4-1BB, belongs to the group of co-stimulatory immune receptors and is a member of the TNF receptor superfamily (TNFRSF). It is preferentially found on activated T-cells and regulatory T-cells. In T-cells, CD137-crosslinking delivers a potent co-stimulatory signal as it promotes T-cell proliferation, formation of memory cells and enhances survival. Despite numerous studies investigating the effects of co-stimulatory CD137 in T-cells, little is known regarding the role of CD137 in human monocytes/macrophages. To investigate the effect of CD137 triggering on human monocytes, monocytes were isolated and treated with an agonistic CD137 mAb and subsequently analyzed by RNA-seq.

2021-06-17 | GSE171108 | GEO

Anti-CD137 drives early epigenetic remodeling of Tex cell associated genes

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2025-06-06 | GSE228271 | GEO

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