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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 -
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 -
Trends in Immunology Dec 2023A binary classification of macrophage activation as inflammatory or resolving does not capture the diversity of macrophage states observed in tissues. However, framing... (Review)
Review
A binary classification of macrophage activation as inflammatory or resolving does not capture the diversity of macrophage states observed in tissues. However, framing macrophage activation as a continuous spectrum of states overlooks the intracellular and extracellular networks that regulate and coordinate macrophage responses. Here, we suggest that the systems biology concept of network motifs, which incorporate rules of local molecular interactions, is useful for reframing macrophage activation. Because network motifs can be used to regulate distinct biological functions, they offer a simplified unit that can be compared across organismal, tissue, and disease contexts. Moreover, defining macrophage states as combinations of functional modules regulated by network motifs offers a framework to ultimately predict and target macrophage responses arising in complex environments.
Topics: Humans; Macrophages; Phagocytosis; Systems Biology; Inflammation; Macrophage Activation
PubMed: 37949786
DOI: 10.1016/j.it.2023.10.009 -
Current Opinion in Biotechnology Apr 2021Macrophages are the prominent innate immune cells to combat infection and then restore tissue homeostasis after clearance of pathogens. Intracellular metabolic... (Review)
Review
Macrophages are the prominent innate immune cells to combat infection and then restore tissue homeostasis after clearance of pathogens. Intracellular metabolic reprogramming is required for macrophage activation and function, as such adaptations confer macrophages with sufficient energy and metabolites to support biosynthesis and diverse functions. During the last 10 years, knowledge in this field has been greatly extended by outstanding advances demonstrating that several metabolic intermediates possess the ability to directly control macrophage activation and effector functions by various mechanisms. Of note, citrate and succinate contribute to the inflammatory activation of macrophages while tricarboxylic acid cycle-derived metabolite itaconate has a variety of immunomodulatory effects. Such progress not only encourages a further exploration into the emerging new area immunometabolism, but also provides potential therapeutic targets to control unwanted inflammation due to infection.
Topics: Citric Acid Cycle; Humans; Inflammation; Macrophage Activation; Macrophages; Succinic Acid
PubMed: 33610128
DOI: 10.1016/j.copbio.2021.01.020 -
Trends in Immunology Jun 2021Tissue-resident macrophages (M) have recently emerged as a key rheostat capable of regulating the balance between organ health and disease. In most organs,... (Review)
Review
Tissue-resident macrophages (M) have recently emerged as a key rheostat capable of regulating the balance between organ health and disease. In most organs, ontogenetically and functionally distinct macrophage subsets fulfill a plethora of functions specific to their tissue environment. In this review, we summarize recent findings regarding the ontogeny and functions of macrophage populations in different mammalian tissues, describing how these cells regulate tissue homeostasis and how they can contribute to inflammation. Furthermore, we highlight new developments concerning certain general principles of tissue macrophage biology, including the importance of metabolism for understanding macrophage activation states and the influence of intrinsic and extrinsic factors on macrophage metabolic control. We also shed light on certain open questions in the field and how answering these might pave the way for tissue-specific therapeutic approaches.
Topics: Animals; Homeostasis; Inflammation; Macrophage Activation; Macrophages
PubMed: 33972166
DOI: 10.1016/j.it.2021.04.007 -
Journal of Experimental & Clinical... Jul 2018Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment...
BACKGROUND
Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC).
METHODS
Conditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms.
RESULTS
THP-1-derived and PBMCs derived macrophages exhibited an M1-like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells.
CONCLUSIONS
We proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC.
Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Cell Proliferation; Culture Media, Conditioned; Exosomes; Humans; Immunohistochemistry; MAP Kinase Signaling System; Macrophage Activation; Macrophages; Molecular Imaging; Mouth Neoplasms; Thrombospondin 1; Tumor Microenvironment
PubMed: 29986759
DOI: 10.1186/s13046-018-0815-2 -
Cardiovascular Research Jul 2023
Topics: Humans; Macrophages; Atherosclerosis; Macrophage Activation; Plaque, Atherosclerotic
PubMed: 37226046
DOI: 10.1093/cvr/cvad072 -
Results and Problems in Cell... 2017Macrophages constitute a heterogeneous population of myeloid cells that are essential for maintaining homeostasis and as a first line of innate responders controlling... (Review)
Review
Macrophages constitute a heterogeneous population of myeloid cells that are essential for maintaining homeostasis and as a first line of innate responders controlling and organizing host defenses against pathogens. Monocyte-macrophage lineage cells are among the most functionally diverse and plastic cells of the immune system. They undergo specific activation into functionally distinct phenotypes in response to immune signals and microbial products. In mammals, macrophage functional heterogeneity is defined by two activation states, M1 and M2, which represent two polar ends of a continuum exhibiting pro-inflammatory and tissue repair activities, respectively. While the ancient evolutionary origin of macrophages as phagocytic defenders is well established, the evolutionary roots of the specialized division of macrophages into subsets with polarized activation phenotypes is less well defined. Accordingly, this chapter focuses on recent advances in the understanding of the evolution of macrophage polarization and functional heterogeneity with a focus on ectothermic vertebrates.
Topics: Animals; Cell Lineage; Humans; Macrophage Activation; Macrophages
PubMed: 28455703
DOI: 10.1007/978-3-319-54090-0_1 -
Journal of Immunology Research 2020Atherosclerosis (AS), a typical chronic inflammatory vascular disease, is the main pathological basis of ischemic cardio/cerebrovascular disease (CVD). Long-term... (Review)
Review
Atherosclerosis (AS), a typical chronic inflammatory vascular disease, is the main pathological basis of ischemic cardio/cerebrovascular disease (CVD). Long-term administration was characterized with low efficacy and serious side effects, while the macrophages with attractive intrinsic homing target have great potential in the efficient and safe management of AS. In this review, we focused on the systematical summary of the macrophage-based therapies in AS management, including macrophage autophagy, polarization, targeted delivery, microenvironment-triggered drug release, and macrophage- or macrophage membrane-based drug carrier. In conclusion, macrophage-based therapies have great promise to effectively manage AS in future research and clinic translation.
Topics: Animals; Atherosclerosis; Autophagy; Cardiovascular Agents; Cell Membrane; Disease Models, Animal; Drug Carriers; Humans; Inflammasomes; Macrophage Activation; Macrophages
PubMed: 32411803
DOI: 10.1155/2020/8131754 -
Seminars in Immunology Oct 2016Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in... (Review)
Review
Macrophages are heterogeneous cells that play a key role in inflammatory and tissue reparative responses. Over the past decade it has become clear that shifts in cellular metabolism are important determinants of macrophage function and phenotype. At the same time, our appreciation of macrophage diversity in vivo has also been increasing. Factors such as cell origin and tissue localization are now recognized as important variables that influence macrophage biology. Whether different macrophage populations also have unique metabolic phenotypes has not been extensively explored. In this article, we will discuss the importance of understanding how macrophage origin can modulate metabolic programming and influence inflammatory responses.
Topics: Animals; Energy Metabolism; Gene Expression Regulation; Humans; Immunomodulation; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Organ Specificity; Phenotype
PubMed: 27771140
DOI: 10.1016/j.smim.2016.10.004