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Proceedings of the National Academy of... Apr 2021Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor...
Macrophages are the key regulator of T-cell responses depending on their activation state. C-C motif chemokine receptor-like 2 (CCRL2), a nonsignaling atypical receptor originally cloned from LPS-activated macrophages, has recently been shown to regulate immune responses under several inflammatory conditions. However, whether CCRL2 influences macrophage function and regulates tumor immunity remains unknown. Here, we found that tumoral CCRL2 expression is a predictive indicator of robust antitumor T-cell responses in human cancers. CCRL2 is selectively expressed in tumor-associated macrophages (TAM) with immunostimulatory phenotype in humans and mice. Conditioned media from tumor cells could induce CCRL2 expression in macrophages primarily via TLR4, which is negated by immunosuppressive factors. mice exhibit accelerated melanoma growth and impaired antitumor immunity characterized by significant reductions in immunostimulatory macrophages and T-cell responses in tumor. Depletion of CD8 T cells or macrophages eliminates the difference in tumor growth between WT and mice. Moreover, CCRL2 deficiency impairs immunogenic activation of macrophages, resulting in attenuated antitumor T-cell responses and aggravated tumor growth in a coinjection tumor model. Mechanically, CCRL2 interacts with TLR4 on the cell surface to retain membrane TLR4 expression and further enhance its downstream Myd88-NF-κB inflammatory signaling in macrophages. Similarly, mice exhibit reduced CCRL2 expression in TAM and accelerated melanoma growth. Collectively, our study reveals a functional role of CCRL2 in activating immunostimulatory macrophages, thereby potentiating antitumor T-cell response and tumor rejection, and suggests CCLR2 as a potential biomarker candidate and therapeutic target for cancer immunotherapy.
Topics: Animals; CD8-Positive T-Lymphocytes; China; Female; Immunization; Macrophage Activation; Male; Melanoma; Mice; NF-kappa B; Neoplasms; Receptors, CCR; Signal Transduction; T-Lymphocytes; Toll-Like Receptor 4; Tumor-Associated Macrophages
PubMed: 33846258
DOI: 10.1073/pnas.2024171118 -
Life Sciences Feb 2021We will investigate the anti-inflammatory activities of berberine (BBR) in treating chronic atrophic gastritis (CAG) induced by Helicobacter pylori (H. pylori)....
AIMS
We will investigate the anti-inflammatory activities of berberine (BBR) in treating chronic atrophic gastritis (CAG) induced by Helicobacter pylori (H. pylori). Furthermore, the underlying molecular mechanisms of BBR also will be explored systematically.
MATERIALS AND METHODS
Rats were infected by H. pylori. Lipopolysaccharide (LPS) and H. pylori were applied to induce M1 Mφs polarization, interleukin 4 (IL-4) and BBR were used to induce M2 Mφs polarization. Supernatants of polarized Mφs were collected as conditioned media (CM) for investigating the impact of Mφs and its' secreted cytokine on gastric epithelial cells (GES-1). Cell viability, morphology, proliferation, and quantitative analysis of RAW 264.7 cells and GES-1 cells were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression were measured.
KEY FINDINGS
BBR inhibited M1-polarized Mφs, which was induced by H. pylori and LPS, and advocated M2-polarized Mφs. The M1-specific markers (TNF-α and IFN-γ) in supernatants were reduced significantly and M2 specific markers (TGF-β and IL-10) were increased obviously under BBR intervention. In addition, BBR significantly protected GES-1 from M1-polarized Mφs injury. The mRNA expression of M1-polarized Mφs, including TNF-α, NOS2, CCR7, and IRF-8, were suppressed by BBR administration and the mRNA expression of M2-polarized Mφs, including IL-4, STAT6, IL-10 and Chil3, were increased by BBR intervention. Meanwhile, BBR activated IL-4-STAT6 signaling pathway in vivo and in vitro when H. pylori infection and presented anti-inflammatory activities.
SIGNIFICANCE
BBR promotes M2-polarized Mφs when H. pylori infection. The anti-inflammatory properties of BBR tightly related to M1-polarized Mφs inhibition and M2-polarized Mφs promotion. BBR activates IL-4-STAT6 signaling pathway, which is crucial exceedingly in M2 Mφs activation and anti-inflammatory response.
Topics: Animals; Berberine; Gastritis, Atrophic; Gene Expression Regulation; Helicobacter Infections; Helicobacter pylori; Humans; Interleukin-4; Macrophage Activation; Male; Mice; Rats; STAT6 Transcription Factor
PubMed: 33340526
DOI: 10.1016/j.lfs.2020.118903 -
Frontiers in Cellular and Infection... 2021Acute lung injury (ALI) induced by sepsis is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to...
Acute lung injury (ALI) induced by sepsis is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to uncontrolled pulmonary inflammation. However, effective treatments for ALI are unavailable. The exact mechanism by which the initial mediator of alveolar epithelial cells (AECs) induces inflammation remains elusive. Here we investigated the roles of AEC-derived exosomes in AM activation and sepsis-induced ALI and . Cecal ligation and puncture (CLP) was utilized to establish septic lung injury model in rats. The effect of exosomal inhibition by intratracheal GW4869 administration on lung injury was investigated. To assess the effects of AEC-derived exosomes on ALI, we treated the rat alveolar epithelial cell line RLE-6TN with LPS to induce cell damage. Exosomes from conditioned medium of LPS-treated AECs (LPS-Exos) were isolated by ultracentrifugation. The miRNAs in LPS-Exos were screened by miRNA expression profile analysis. The effects of miR-92a-3p on the function of AMs were studied. We found that intratracheal GW4869 administration ameliorated lung injury following CLP-induced ALI. LPS-Exos were taken up by AMs and activated these cells. Consistently, administration of LPS-Exos in rats significantly aggravated pulmonary inflammation and alveolar permeability. Moreover, miR-92a-3p was enriched in LPS-Exos and could be delivered to AMs. Inhibition of miR-92a-3p in AECs diminished the proinflammatory effects of LPS-Exos and . Mechanistically, miR-92a-3p activates AMs along with pulmonary inflammation. This process results in activation of the NF-κB pathway and downregulation of PTEN expression, which was confirmed by a luciferase reporter assay. In conclusion, AEC-derived exosomes activate AMs and induce pulmonary inflammation mediated by miR-92a-3p in ALI. The present findings revealed a previously unidentified role of exosomal miR-92a-3p in mediating the crosstalk between injured AEC and AMs. miR-92a-3p in AEC exosomes might represent a novel diagnostic biomarker for ALI, which may lead to a new therapeutic approach.
Topics: Acute Lung Injury; Alveolar Epithelial Cells; Animals; Exosomes; Macrophage Activation; Macrophages, Alveolar; MicroRNAs; Rats; Sepsis
PubMed: 34041043
DOI: 10.3389/fcimb.2021.646546 -
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 -
Transplant Immunology Apr 2022Transplant rejection is one of the primary factors leading to loss of allograft function, and macrophages are involved in allograft rejection. Macrophages polarize into... (Review)
Review
Transplant rejection is one of the primary factors leading to loss of allograft function, and macrophages are involved in allograft rejection. Macrophages polarize into different phenotypes according to stimulation by different external factors. Different types of macrophages play distinct roles in inflammation, tumors, and autoimmune diseases and are involved in transplant rejection. In this review, we introduce the origin and migration of macrophages, outline the classification of macrophages and their polarization mechanisms, and review the currently understood mechanisms of their involvement in transplant rejection. Finally, we discuss the regulation of macrophage polarization and miRNA expression with respect to transplant rejection, which is important for the development of new anti-rejection therapies.
Topics: Graft Rejection; Humans; Inflammation; Macrophage Activation; Macrophages; Transplantation, Homologous
PubMed: 35017096
DOI: 10.1016/j.trim.2022.101536 -
Journal of Innate Immunity 2022Macrophages, the central mediators of innate immune responses, being in the first-line of defense, they have to readily respond to pathogenic or tissue damage signals to... (Review)
Review
Macrophages, the central mediators of innate immune responses, being in the first-line of defense, they have to readily respond to pathogenic or tissue damage signals to initiate the inflammatory cascade. Such rapid responses require energy to support orchestrated production of pro-inflammatory mediators and activation of phagocytosis. Being a cell type that is present in diverse environments and conditions, macrophages have to adapt to different nutritional resources. Thus, macrophages have developed plasticity and are capable of utilizing energy at both normoxic and hypoxic conditions and in the presence of varying concentrations of glucose or other nutrients. Such adaptation is reflected on changes in signaling pathways that modulate responses, accounting for the different activation phenotypes observed. Macrophage metabolism has been tightly associated with distinct activation phenotypes within the range of M1-like and M2-like types. In the context of diseases, systemic changes also affect macrophage metabolism, as in diabetes and insulin resistance, which results in altered metabolism and distinct activation phenotypes in the adipose tissue or in the periphery. In the context of solid tumors, tumor-associated macrophages adapt in the hypoxic environment, which results in metabolic changes that are reflected on an activation phenotype that supports tumor growth. Coordination of environmental and pathogenic signals determines macrophage metabolism, which in turn shapes the type and magnitude of the response. Therefore, modulating macrophage metabolism provides a potential therapeutic approach for inflammatory diseases and cancer.
Topics: Adipose Tissue; Humans; Immunity, Innate; Inflammation; Insulin Resistance; Macrophage Activation; Macrophages
PubMed: 34247159
DOI: 10.1159/000516780 -
Biochimica Et Biophysica Acta.... Jan 2022Macrophages are professional phagocytes, indispensable for maintenance of tissue homeostasis and integrity. Depending on their resident tissue, macrophages are exposed... (Review)
Review
Macrophages are professional phagocytes, indispensable for maintenance of tissue homeostasis and integrity. Depending on their resident tissue, macrophages are exposed to highly diverse metabolic environments. Adapted to their niche, they can contribute to local metabolic turnover through metabolite uptake, conversion, storage and release. Disturbances in tissue homeostasis caused by infection, inflammation or damage dramatically alter the local milieu, impacting macrophage activation status and metabolism. In the case of persisting stimuli, defective macrophage responses ensue, which can promote tissue damage and disease. Especially relevant herein are disbalances in lipid rich environments, where macrophages are crucially involved in lipid uptake and turnover, preventing lipotoxicity. Lipid uptake is to a large extent facilitated by macrophage expressed scavenger receptors that are dynamically regulated and important in many metabolic diseases. Here, we review the receptors mediating lipid uptake and summarize recent findings on their role in health and disease. We further highlight the underlying pathways driving macrophage lipid acquisition and their impact on myeloid metabolic remodelling.
Topics: Biological Transport; Homeostasis; Humans; Inflammation; Lipids; Macrophage Activation; Macrophages
PubMed: 34626791
DOI: 10.1016/j.bbalip.2021.159066 -
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 -
Cold Spring Harbor Perspectives in... Dec 2022Monocytes/macrophages are key components of the body's innate ability to restore tissue function after injury. In most tissues, both embryo-derived tissue-resident... (Review)
Review
Monocytes/macrophages are key components of the body's innate ability to restore tissue function after injury. In most tissues, both embryo-derived tissue-resident macrophages and recruited blood monocyte-derived macrophages contribute to the injury response. The developmental origin of injury-associated macrophages has a major impact on the outcome of the healing process. Macrophages are abundant at all stages of repair and coordinate the progression through the different phases of healing. They are highly plastic cells that continuously adapt to their environment and acquire phase-specific activation phenotypes. Advanced omics methodologies have revealed a vast heterogeneity of macrophage activation phenotypes and metabolic status at injury sites in different organs. In this review, we highlight the role of the developmental origin, the link between the wound phase-specific activation state and metabolic reprogramming as well as the fate of macrophages during the resolution of the wounding response.
Topics: Macrophages; Macrophage Activation; Wound Healing
PubMed: 36041784
DOI: 10.1101/cshperspect.a041216 -
Proceedings of the National Academy of... Feb 2020Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and...
Inflammatory bowel disease (IBD) comprises chronic relapsing disorders of the gastrointestinal tract characterized pathologically by intestinal inflammation and epithelial injury. Here, we uncover a function of extracellular matrix protein 1 (ECM1) in promoting the pathogenesis of human and mouse IBD. ECM1 was highly expressed in macrophages, particularly tissue-infiltrated macrophages under inflammatory conditions, and ECM1 expression was significantly induced during IBD progression. The macrophage-specific knockout of ECM1 resulted in increased arginase 1 (ARG1) expression and impaired polarization into the M1 macrophage phenotype after lipopolysaccharide (LPS) treatment. A mechanistic study showed that ECM1 can regulate M1 macrophage polarization through the granulocyte-macrophage colony-stimulating factor/STAT5 signaling pathway. Pathological changes in mice with dextran sodium sulfate-induced IBD were alleviated by the specific knockout of the gene in macrophages. Taken together, our findings show that ECM1 has an important function in promoting M1 macrophage polarization, which is critical for controlling inflammation and tissue repair in the intestine.
Topics: Animals; Arginase; Disease Models, Animal; Extracellular Matrix Proteins; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammatory Bowel Diseases; Intestines; Lipopolysaccharides; Macrophage Activation; Macrophages; Mice; Mice, Knockout; STAT5 Transcription Factor; Signal Transduction
PubMed: 31980528
DOI: 10.1073/pnas.1912774117