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Nature Mar 2024Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when...
Tiragolumab, an anti-TIGIT antibody with an active IgG1κ Fc, demonstrated improved outcomes in the phase 2 CITYSCAPE trial (ClinicalTrials.gov: NCT03563716 ) when combined with atezolizumab (anti-PD-L1) versus atezolizumab alone. However, there remains little consensus on the mechanism(s) of response with this combination. Here we find that a high baseline of intratumoural macrophages and regulatory T cells is associated with better outcomes in patients treated with atezolizumab plus tiragolumab but not with atezolizumab alone. Serum sample analysis revealed that macrophage activation is associated with a clinical benefit in patients who received the combination treatment. In mouse tumour models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes and dendritic cells through Fcγ receptors (FcγR), in turn driving anti-tumour CD8 T cells from an exhausted effector-like state to a more memory-like state. These results reveal a mechanism of action through which TIGIT checkpoint inhibitors can remodel immunosuppressive tumour microenvironments, and suggest that FcγR engagement is an important consideration in anti-TIGIT antibody development.
Topics: Animals; Humans; Mice; Antibodies, Monoclonal; Antineoplastic Agents; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Dendritic Cells; Drug Therapy, Combination; Immune Checkpoint Inhibitors; Macrophage Activation; Myeloid Cells; Neoplasms; Receptors, IgG; Receptors, Immunologic; T-Lymphocytes, Regulatory; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 38418879
DOI: 10.1038/s41586-024-07121-9 -
Theranostics 2023Liver fibrosis is the common pathological pathway of chronic liver diseases and its mechanisms of which have not been fully declared. Macrophages play essential roles...
Liver fibrosis is the common pathological pathway of chronic liver diseases and its mechanisms of which have not been fully declared. Macrophages play essential roles in progression of liver fibrosis partially by sensing abnormal mechanical signals. The aim of the study is to investigate the functions of macrophage Piezo1, a mechano-sensitive ion channel, in liver fibrosis. Immunofluorescence in human and murine fibrotic liver samples revealed that expression of macrophage Piezo1 was increased. Myeloid-specific knockout () attenuated liver fibrosis by decreased collagen deposition and epithelial-mesenchymal transition (EMT). In mice, less inflammation during development of liver fibrosis was observed by lessened macrophage infiltration, decreased M1 polarization and expression of inflammatory cytokines. RNA-seq data showed macrophage Piezo1 regulated transcription of cathepsin S (CTSS). inhibited expression and activity of CTSS and and regulated T cell activity. Furthermore, inhibition of CTSS reversed macrophage inflammatory response driven by Piezo1 activation and LPS. Macrophage Piezo1 activation promoted CTSS secretion due to increased activity of Ca-dependent calpain protease induced by Ca influx to cleave lysosome-associated membrane protein-1 (LAMP1). Pharmacological inhibition of calpain activity partially blocked Piezo1 mediated CTSS secretion. Macrophage Piezo1 deficiency limits the progression of liver fibrosis by inhibited inflammatory response and decreased secretion of CTSS. These findings suggest that targeting Piezo1 channel may be a potential strategy for treating hepatic fibrosis.
Topics: Animals; Humans; Mice; Calpain; Cytokines; Fibrosis; Ion Channels; Liver Cirrhosis; Macrophages
PubMed: 37908726
DOI: 10.7150/thno.86103 -
Cell Proliferation Sep 2023Macrophages are multifunctional immune system cells that are essential for the mechanical stimulation-induced control of metabolism. Piezo1 is a non-selective calcium...
Macrophages are multifunctional immune system cells that are essential for the mechanical stimulation-induced control of metabolism. Piezo1 is a non-selective calcium channel expressed in multifarious tissues to convey mechanical signals. Here, a cellular model of tension was used to study the effect of mechanical stretch on the phenotypic transformation of macrophages and its mechanism. An indirect co-culture system was used to explore the effect of macrophage activation on bone marrow mesenchymal stem cells (BMSCs), and a treadmill running model was used to validate the mechanism in vivo for in vitro studies. p53 was acetylated and deacetylated by macrophages as a result of mechanical strain being detected by Piezo1. This process is able to polarize macrophages towards M2 and secretes transforming growth factor-beta (TGF-β1), which subsequently stimulates BMSCs migration, proliferation and osteogenic differentiation. Knockdown of Piezo1 inhibits the conversion of macrophages to the reparative phenotype, thereby affecting bone remodelling. Blockade of TGF-β I, II receptors and Piezo1 significantly reduced exercise-increased bone mass in mice. In conclusion, we showed that mechanical tension causes calcium influx, p53 deacetylation, macrophage polarization towards M2 and TGF-β1 release through Piezo1. These events support BMSC osteogenesis.
Topics: Mice; Animals; Osteogenesis; Transforming Growth Factor beta1; Mechanotransduction, Cellular; Tumor Suppressor Protein p53; Macrophages; Cell Differentiation; Ion Channels
PubMed: 36880296
DOI: 10.1111/cpr.13440 -
Nature Communications Nov 2023N-methyladenosine (mA), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of mA in allergic...
N-methyladenosine (mA), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of mA in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that mA methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, mA-sequencing shows that loss of METTL3 impairs the mA-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-mA/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of mA in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.
Topics: Humans; Asthma; Homeostasis; Inflammation; Macrophages; Methylation; Methyltransferases; Phosphatidylinositol 3-Kinases; RNA; RNA, Messenger
PubMed: 37957139
DOI: 10.1038/s41467-023-43219-w -
The Journal of Clinical Investigation Nov 2023Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the...
Macrophages are key mediators of innate immunity whose functional state can be regulated by glucose transporters. Although abundantly expressed in macrophages, the specific function of GLUT3, an isoform of facilitative glucose transporters, has not been clearly established. In this issue of the JCI, Dong-Min Yu and colleagues identify an alternative role for GLUT3 in promoting M2 macrophage polarization. The authors demonstrated that GLUT3 was upregulated upon M2 stimulation and was required for efficient alternative macrophage polarization and function. They further showed that GLUT3-induced M2 polarization was independent of glucose transport and functioned through Ras-mediated regulation of IL-4R endocytosis and IL-4/STAT6 activation. These findings may guide the development of macrophage-targeted treatments.
Topics: Glucose Transporter Type 3; Macrophages; Signal Transduction; Glucose; Macrophage Activation
PubMed: 37909335
DOI: 10.1172/JCI174540 -
The Journal of Clinical Investigation Dec 2023Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both...
Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-octyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.
Topics: Mice; Humans; Animals; NF-E2-Related Factor 2; Macrophages; Atherosclerosis; Inflammation; Aortic Diseases; Succinates
PubMed: 38085578
DOI: 10.1172/JCI173034 -
Nature Communications Apr 2024Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis....
Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.
Topics: Humans; Histones; Lysine; Macrophage Activation; Kidney Diseases; Kidney; Cellular Senescence; Epithelial Cells; Interleukin-1beta; Acetate-CoA Ligase
PubMed: 38615014
DOI: 10.1038/s41467-024-47315-3 -
Science Advances Nov 2023BMP15 is a conserved regulator of ovarian development and maintenance in vertebrates. In humans, premature ovarian insufficiency is caused by autoimmunity and genetic...
BMP15 is a conserved regulator of ovarian development and maintenance in vertebrates. In humans, premature ovarian insufficiency is caused by autoimmunity and genetic factors, including mutation of BMP15. The cellular mechanisms underlying ovarian failure caused by BMP15 mutation and immune contributions are not understood. Using zebrafish, we established a causal link between macrophage activation and ovarian failure, which, in zebrafish, causes sex reversal. We define a germline-soma signaling axis that activates macrophages and drives ovarian failure and female-to-male sex reversal. Germline loss of zebrafish Bmp15 impairs oogenesis and initiates this cascade. Single-cell RNA sequencing and genetic analyses implicate ovarian somatic cells that express conserved macrophage-activating ligands as mediators of ovarian failure and sex reversal. Genetic ablation of macrophages or elimination of Csf1Rb ligands, Il34 or Csf1a, delays or blocks premature oocyte loss and sex reversal. The axis identified here provides insight into the cells and pathways governing oocyte and ovary maintenance and potential therapeutic targets to preserve female fertility.
Topics: Humans; Animals; Male; Female; Zebrafish; Macrophage Activation; Oocytes; Primary Ovarian Insufficiency
PubMed: 37992158
DOI: 10.1126/sciadv.adg7488 -
Cellular & Molecular Immunology May 2024Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in...
Phosphoglycerate dehydrogenase (PHGDH) has emerged as a crucial factor in macromolecule synthesis, neutralizing oxidative stress, and regulating methylation reactions in cancer cells, lymphocytes, and endothelial cells. However, the role of PHGDH in tumor-associated macrophages (TAMs) is poorly understood. Here, we found that the T helper 2 (Th2) cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation. Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration, which are essential for immunosuppressive macrophages. Mechanistically, PHGDH-mediated serine biosynthesis promotes α-ketoglutarate production, which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment. Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth, reduced TAM infiltration, a phenotypic shift of M2-like TAMs toward an M1-like phenotype, downregulated PD-L1 expression and enhanced antitumor T-cell immunity. Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.
Topics: Animals; Tumor-Associated Macrophages; Mechanistic Target of Rapamycin Complex 1; Phosphoglycerate Dehydrogenase; Signal Transduction; Mice; Tumor Microenvironment; Ketoglutaric Acids; Humans; Mice, Inbred C57BL; Phenotype; Cell Line, Tumor; Macrophage Activation
PubMed: 38409249
DOI: 10.1038/s41423-024-01134-0 -
Frontiers in Immunology 2023Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH), have emerged as significant contributors... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH), have emerged as significant contributors to hepatic morbidity worldwide. The pathophysiology of NAFLD/NASH is multifaceted, variable, and remains incompletely understood. The pivotal role of liver-resident and recruited macrophages in the pathogenesis of NAFLD and NASH is widely acknowledged as a crucial factor in innate immunity. The remarkable plasticity of macrophages enables them to assume diverse activation and polarization states, dictated by their immunometabolism microenvironment and functional requirements. Recent studies in the field of immunometabolism have elucidated that alterations in the metabolic profile of macrophages can profoundly influence their activation state and functionality, thereby influencing various pathological processes. This review primarily focuses on elucidating the polarization and activation states of macrophages, highlighting the correlation between their metabolic characteristics and the transition from pro-inflammatory to anti-inflammatory phenotypes. Additionally, we explore the potential of targeting macrophage metabolism as a promising therapeutic approach for the management of NAFLD/NASH.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Macrophages; Anti-Inflammatory Agents
PubMed: 37868954
DOI: 10.3389/fimmu.2023.1257596