Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

ABSTRACT: Necroptosis contributes to hepatocyte death (HC) in non-alcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs is associated with worsening NASH in humans and in mice with diet-induced NASH and that NASH liver showed evidence of impaired necHC clearance by liver macrophages. Further, the "don't-eat-me" ligand CD47 on HCs and its receptor, SIRPα, on liver macrophages, were markedly upregulated in human and mouse NASH. In vitro, anti-CD47 or anti-SIRPα promoted necHC engulfment by primary liver macrophages. In a proof-of-concept mouse model of inducible HC necroptosis, anti-CD47 increased necHC uptake by liver macrophages and inhibited hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Most importantly, treatment of two mouse models of diet-induced NASH with anti-CD47 or anti-SIRPα increased the uptake of necHC by liver macrophages and decreased HSC activation and liver fibrosis. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα upregulation contributes to fibrotic NASH and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE197111 | GEO | 2022/11/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

Project description:CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

| PRJNA808993 | ENA

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (mRNA)

Project description:Macrophages efferocytosis of apoptotic osteoblasts (apoOBs) is a key osteoimmune process for bone homeostasis that is highly regulated in osteoimmune surveillance. However, apoOBs accumulate in aged bone marrow, where they might mount proinflammatory responses and progressive bone loss. Why apoOBs were not cleared during aging remains unknown. Here, we show that apoOBs upregulate immune checkpoint molecule CD47 with age to evade macrophages clearance. Using osteoblast- and myeloid-specific gene knockout mice, we identify histone deacetylase SIRT6 as an essential regulator of the CD47–SIRPα checkpoint. Further, apoOBs that require SIRT6-mediated chemotaxis signals can recruit macrophages by releasing apoptotic extracellular vesicles. Therapeutically, we develop two targeting delivery strategies to enhance SIRT6 activity, showing increased apoOBs clearance and delayed age-related bone loss. Collectively, our data revealed a previously unknown linkage between immune surveillance and bone homeostasis and targeting the mechanism of SIRT6-regulated apoOBs clearance could be a promising therapeutic strategy for age-related bone diseases.

2022-09-22 | GSE213675 | GEO

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (miRNA)

2022-04-30 | GSE201649 | GEO

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (mRNA)

2022-04-30 | GSE201650 | GEO

Impaired efferocytosis enables apoptotic osteoblasts to escape osteoimmune surveillance during aging (ChIP-seq)

2022-09-22 | GSE213674 | GEO

Engineered CD47 protects T cells for enhanced antitumor immunity

Project description:Adoptively transferred T cells and agents designed to block the CD47/SIRPalpha axis are promising cancer therapeutics that activate distinct arms of the immune system. We administered anti-CD47 with adoptively transferred T cells with the goal of enhancing antitumor efficacy but observed rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors, which abrogated therapeutic benefit. anti-CD47 mediated CAR T clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered a CD47 variant (47E) that engaged SIRPalpha and provided a “don’t-eat-me” signal that was not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E were resistant to clearance by macrophages following anti-CD47, and mediated significant, sustained macrophage recruitment into the TME. Although many of the recruited macrophages manifested an M2-like profile, the combined therapy synergistically enhanced antitumor efficacy. This work identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T cell directed therapeutics with those designed to activate macrophages. It further delivers a therapeutic approach capable of simultaneously harnessing the antitumor effects of T cells and macrophages that manifests enhanced potency against solid tumors.

2024-03-13 | GSE261475 | GEO

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 2]

Project description:Type I interferons (IFN-Is) have been well recognized for their roles in immune cells in tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation (OXPHOS) is typically latent in tumor cells. However, whether OXPHOS can be targeted for immunotherapy remains unclear. Here, we found that tumor cell responsiveness to IFN-Is is essential for CD47-SIRPα blockade immunotherapy. Interestingly, IFN-Is directly reprogram tumor cell metabolism by activating OXPHOS for ATP production via ISG15. ATP extracellular release is also enhanced by IFN-Is via autophagy. Tumor cells with a genetic deficiency in OXPHOS or autophagy were resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade primes the anti-tumor T cell response via ATP-P2X7 receptor-mediated dendritic cell activation. Further combination with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, showed synergistic anti-tumor effects. Together, these data reveal the unrecognized mechanisms of IFN-Is on tumor cell metabolic reprograming in tumor immunotherapy and provide novel strategies harnessing this pathway for enhanced efficacy of CD47-SIRPα blockade.

2024-06-04 | GSE235112 | GEO

Expression data from mouse brain mononuclear cells

Project description:A membrane protein SIRPα (CD172a) interacts with another membrane protein CD47 and thereby constitutes a cell–cell contact signal. To investigate the functional role of CD47-SIRPα signal in the brain, we analyzed the effect of genetic ablation of CD47-SIRPα signal on the gene expression profile in specific brain cells by the use of microarrays.

2019-03-22 | GSE118805 | GEO

Expression data from mouse optic nerve and optic tract

2019-03-22 | GSE118804 | GEO

SIRPα-CD47 axis regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism.

Project description:Type-2 innate lymphoid cells (ILC2) are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma. In this study, we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha (SIRPα), which interacts with CD47, in controlling ILC2-mediated airway hyperreactivity (AHR). Our data indicate that activated ILC2s upregulate the expression of SIRPα, and the interaction between SIRPα and CD47 effectively suppresses both ILC2 proliferation and effector function. To evaluate the efficacy of SIRPα in regulating ILC2-mediated AHR, we utilized SIRPα and CD47 deficient mice in a murine model of allergen-induced AHR. Our findings suggest that the absence of SIRPα leads to the overactivation of ILC2s. Conversely, engagement with SIRPα reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR. Furthermore, the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways, thereby regulating NF-κB activity and the production of type two cytokines. Additionally, our studies on human cells have revealed that SIRPα is inducible and expressed on human ILC2s, and administration of a SIRPα agonist effectively suppresses the effector function and cytokine production of ILC2s. Moreover, administering human CD47-Fc to humanized ILC2 mice effectively alleviated AHR and lung inflammation. These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.

2024-08-10 | GSE264061 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data