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International Journal of Molecular... Jul 2023Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate... (Review)
Review
Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid β-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.
Topics: Lipid Metabolism; Cell Polarity; Inflammation; Neoplasms; Macrophages; Cholesterol; Fatty Acids; Ferroptosis; Humans
PubMed: 37569407
DOI: 10.3390/ijms241512032 -
Theranostics 2023Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aβ accumulation and tau...
Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aβ accumulation and tau hyperphosphorylation. Currently, there is no effective cure available for AD. The astrocyte AQP4 polarized distribution-mediated glymphatic system is essential for Aβ and abnormal tau clearance and is a potential therapeutic target for AD. However, the role of exercise on the AQP4 polarized distribution and the association between the AQP4 polarized distribution and astrocyte phenotype polarization are poorly understood. Using a streptozotocin (STZ)-induced sporadic AD rat model, we investigated the effects of high-intensity interval training on AD pathologies. The Branes maze task was conducted to measure spatial learning and memory. Immunofluorescence staining of NeuN with TUNEL, Fluoro-Jade C, and relative neuronal damage markers was applied to measure neuronal apoptosis, neurodegeneration, and damage. Sholl analysis was carried out to analyze the morphology of microglia. Line-scan analysis, 3D rendering, and the orthogonal view were applied to analyze the colocalization. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) analysis were conducted to examine AQP4 and Aβ, respectively. An APP/PS1 transgenic AD mice model was used to confirm the key findings. High-intensity interval training (HIIT) alleviates cognitive dysfunction in STZ-induced AD-like rat models and provides neuroprotection against neurodegeneration, neuronal damage, and neuronal loss. Additionally, HIIT improved the drainage of abnormal tau and Aβ from the cortex and hippocampus via the glymphatic system to the kidney. Further mechanistic studies support that the beneficial effects of HIIT on AD might be due, in part, to the polarization of glial cells from a neurotoxic phenotype towards a neuroprotective phenotype. Furthermore, an intriguing finding of our study is that the polarized distribution of AQP4 was strongly correlated with astrocyte phenotype. We found A2 phenotype exhibited more evident AQP4 polarization than the A1 phenotype. Our findings indicate that HIIT ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype and astrocyte phenotype-associated AQP4 polarization. These changes promote Aβ and p-tau clearance from the brain tissue through the glymphatic system and the kidney.
Topics: Animals; Mice; Rats; Alzheimer Disease; Amyloid beta-Peptides; Astrocytes; Disease Models, Animal; High-Intensity Interval Training; Mice, Transgenic; Neurodegenerative Diseases; Phenotype
PubMed: 37351177
DOI: 10.7150/thno.81951 -
Mediators of Inflammation 2023Macrophages are innate immune cells in the organism and can be found in almost tissues and organs. They are highly plastic and heterogeneous cells and can participate in... (Review)
Review
Macrophages are innate immune cells in the organism and can be found in almost tissues and organs. They are highly plastic and heterogeneous cells and can participate in the immune response, thereby playing a crucial role in maintaining the immune homeostasis of the body. It is well known that undifferentiated macrophages can polarize into classically activated macrophages (M1 macrophages) and alternatively activated macrophages (M2 macrophages) under different microenvironmental conditions. The directions of macrophage polarization can be regulated by a series of factors, including interferon, lipopolysaccharide, interleukin, and noncoding RNAs. To elucidate the role of macrophages in various autoimmune diseases, we searched the literature on macrophages with the PubMed database. Search terms are as follows: macrophages, polarization, signaling pathways, noncoding RNA, inflammation, autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, lupus nephritis, Sjogren's syndrome, Guillain-Barré syndrome, and multiple sclerosis. In the present study, we summarize the role of macrophage polarization in common autoimmune diseases. In addition, we also summarize the features and recent advances with a particular focus on the immunotherapeutic potential of macrophage polarization in autoimmune diseases and the potentially effective therapeutic targets.
Topics: Humans; Macrophages; Inflammation; Lupus Nephritis; Arthritis, Rheumatoid; Lupus Erythematosus, Systemic; Macrophage Activation
PubMed: 37332618
DOI: 10.1155/2023/8821610 -
Journal of Inflammation Research 2023Bone homeostasis is a dynamic equilibrium state of bone formation and absorption, ensuring skeletal development and repair. Bone immunity encompasses all aspects of the... (Review)
Review
Bone homeostasis is a dynamic equilibrium state of bone formation and absorption, ensuring skeletal development and repair. Bone immunity encompasses all aspects of the intersection between the skeletal and immune systems, including various signaling pathways, cytokines, and the crosstalk between immune cells and bone cells under both homeostatic and pathological conditions. Therefore, as key cell types in bone immunity, macrophages can polarize into classical pro-inflammatory M1 macrophages and alternative anti-inflammatory M2 macrophages under the influence of the body environment, participating in the regulation of bone metabolism and playing various roles in bone homeostasis. M1 macrophages can not only act as precursors of osteoclasts (OCs), differentiate into mature OCs, but also secrete pro-inflammatory cytokines to promote bone resorption; while M2 macrophages secrete osteogenic factors, stimulating the differentiation and mineralization of osteoblast precursors and mesenchymal stem cells (MSCs), and subsequently increase bone formation. Once the polarization of macrophages is imbalanced, the resulting immune dysregulation will cause inflammatory stimulation, and release a large amount of inflammatory factors affecting bone metabolism, leading to pathological conditions such as osteoporosis (OP), rheumatoid arthritis (RA), and steroid-induced femoral head necrosis (SANFH). In this review, we introduce the signaling pathways and related factors of macrophage polarization, as well as their relationships with immune factors, OB, OC, and MSC. We also discuss the roles of macrophage polarization and bone immunity in various diseases of bone homeostasis imbalance, as well as the factors regulating them, which may help to develop new methods for treating bone metabolic disorders.
PubMed: 37636272
DOI: 10.2147/JIR.S423819 -
Journal of Advanced Research Feb 2024The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction...
INTRODUCTION
The glymphatic system offers a perivascular pathway for the clearance of pathological proteins and metabolites to optimize neurological functions. Glymphatic dysfunction plays a pathogenic role in Parkinson's disease (PD); however, the molecular mechanism of glymphatic dysfunction in PD remains elusive.
OBJECTIVE
To explore whether matrix metalloproteinase-9 (MMP-9)-mediated β-dystroglycan (β-DG) cleavage is involved in the regulation of aquaporin-4 (AQP4) polarity-mediated glymphatic system in PD.
METHODS
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and A53T mice were used in this study. The glymphatic function was evaluated using ex vivo imaging. TGN-020, an AQP4 antagonist, was administered to investigate the role of AQP4 in glymphatic dysfunction in PD. GM6001, an MMP-9 antagonist, was administered to investigate the role of the MMP-9/β-DG pathway in regulating AQP4. The expression and distribution of AQP4, MMP-9, and β-DG were assessed using western blotting, immunofluorescence, and co-immunoprecipitation. The ultrastructure of basement membrane (BM)-astrocyte endfeet was detected using transmission electron microscopy. Rotarod and open-field tests were performed to evaluate motor behavior.
RESULTS
Perivascular influx and efflux of cerebral spinal fluid tracers were reduced in MPTP-induced PD mice with impaired AQP4 polarization. AQP4 inhibition aggravated reactive astrogliosis, glymphatic drainage restriction, and dopaminergic neuronal loss in MPTP-induced PD mice. MMP-9 and cleaved β-DG were upregulated in both MPTP-induced PD and A53T mice, with reduced polarized localization of β-DG and AQP4 to astrocyte endfeet. MMP-9 inhibition restored BM-astrocyte endfeet-AQP4 integrity and attenuated MPTP-induced metabolic perturbations and dopaminergic neuronal loss.
CONCLUSION
AQP4 depolarization contributes to glymphatic dysfunction and aggravates PD pathologies, and MMP-9-mediated β-DG cleavage regulates glymphatic function through AQP4 polarization in PD, which may provide novel insights into the pathogenesis of PD.
Topics: Mice; Animals; Parkinson Disease; Astrocytes; Matrix Metalloproteinase 9; Glymphatic System; Dopamine; Aquaporins
PubMed: 36940850
DOI: 10.1016/j.jare.2023.03.004 -
CNS Neuroscience & Therapeutics Dec 2023Activated microglia can be polarized to the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. Low-intensity pulsed ultrasound (LIPUS) can attenuate...
INTRODUCTION
Activated microglia can be polarized to the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. Low-intensity pulsed ultrasound (LIPUS) can attenuate pro-inflammatory responses in activated microglia.
OBJECTIVE
This study aimed to investigate the effects of LIPUS on M1/M2 polarization of microglial cells and the regulatory mechanisms associated with signaling pathways.
METHODS
BV-2 microglial cells were stimulated by lipopolysaccharide (LPS) to an M1 phenotype or by interleukin-4 (IL-4) to an M2 phenotype. Some microglial cells were exposed to LIPUS, while others were not. M1/M2 marker mRNA and protein expression were measured using real-time polymerase chain reaction and western blot, respectively. Immunofluorescence staining was performed to determine inducible nitric oxide synthase (iNOS)-/arginase-1 (Arg-1)- and CD68-/CD206-positive cells.
RESULTS
LIPUS treatment significantly attenuated LPS-induced increases in inflammatory markers (iNOS, tumor necrosis factor-α, interleukin-1β, and interleukin-6) as well as the expression of cell surface markers (CD86 and CD68) of M1-polarized microglia. In contrast, LIPUS treatment significantly enhanced the expression of M2-related markers (Arg-1, IL-10, and Ym1) and membrane protein (CD206). LIPUS treatment prevented M1 polarization of microglia and enhanced or sustained M2 polarization by regulating M1/M2 polarization through the signal transducer and activator of transcription 1/STAT6/peroxisome proliferator-activated receptor gamma pathways.
CONCLUSIONS
Our findings suggest that LIPUS inhibits microglial polarization and switches microglia from the M1 to the M2 phenotype.
Topics: Humans; Microglia; PPAR gamma; Lipopolysaccharides; STAT1 Transcription Factor; Signal Transduction; Inflammation; STAT6 Transcription Factor
PubMed: 37401041
DOI: 10.1111/cns.14333 -
PeerJ 2023Fibrosis can occur in all major organs with relentless progress, ultimately leading to organ failure and potentially death. Unfortunately, current clinical treatments... (Review)
Review
Fibrosis can occur in all major organs with relentless progress, ultimately leading to organ failure and potentially death. Unfortunately, current clinical treatments cannot prevent or reverse tissue fibrosis. Thus, new and effective antifibrotic therapeutics are urgently needed. In recent years, a growing body of research shows that macrophages are involved in fibrosis. Macrophages are highly heterogeneous, polarizing into different phenotypes. Some studies have found that regulating macrophage polarization can inhibit the development of inflammation and cancer. However, the exact mechanism of macrophage polarization in different tissue fibrosis has not been fully elucidated. This review will discuss the major signaling pathways relevant to macrophage-driven fibrosis and profibrotic macrophage polarization, the role of macrophage polarization in fibrosis of lung, kidney, liver, skin, and heart, potential therapeutics targets, and investigational drugs currently in development, and hopefully, provide a useful review for the future treatment of fibrosis.
Topics: Humans; Fibrosis; Macrophages; Heart; Inflammation; Signal Transduction
PubMed: 37849830
DOI: 10.7717/peerj.16092 -
EMBO Reports Jul 2023The establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning, and formation of neuronal circuits. Here, we show that...
The establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning, and formation of neuronal circuits. Here, we show that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, the loss of Ltk and/or Alk causes a multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk delays neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and axon tracts in the corpus callosum are disrupted. Mechanistically, we show that the loss of Alk and Ltk increases the cell-surface expression and activity of the insulin-like growth factor 1 receptor (Igf-1r), which activates downstream PI3 kinase signaling to drive the excess axon phenotype. Our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioral abnormalities.
Topics: Animals; Mice; Axons; Cell Polarity; Neurogenesis; Neurons; Receptor Protein-Tyrosine Kinases; Signal Transduction
PubMed: 37291945
DOI: 10.15252/embr.202356937 -
Developmental Biology May 2024This review describes in detail the morphological, cytoskeletal and gene expression events leading to the gene regulatory network bifurcation point of trophoblast and... (Review)
Review
This review describes in detail the morphological, cytoskeletal and gene expression events leading to the gene regulatory network bifurcation point of trophoblast and inner cell mass cells in a variety of mammalian preimplantation embryos. The interrelated processes of compaction and polarity establishment are discussed in terms of how they affect YAP/WWTR activity and the location and fate of cells. Comparisons between mouse, human, cattle, pig and rabbit embryos suggest a conserved role for YAP/WWTR signalling in trophoblast induction in eutherian animals though the mechanisms for, and timing of, YAP/WWTR activation differs among species. Downstream targets show further differences, with the trophoblast marker GATA3 being a direct target in all examined mammals, while CDX2-positive and SOX2-negative regulation varies.
PubMed: 38761966
DOI: 10.1016/j.ydbio.2024.05.011 -
Plant Physiology Aug 2023Plant development is a complex task, and many processes involve changes in the asymmetric subcellular distribution of cell components that strongly depend on cell... (Review)
Review
Plant development is a complex task, and many processes involve changes in the asymmetric subcellular distribution of cell components that strongly depend on cell polarity. Cell polarity regulates anisotropic growth and polar localization of membrane proteins and helps to identify the cell's position relative to its neighbors within an organ. Cell polarity is critical in a variety of plant developmental processes, including embryogenesis, cell division, and response to external stimuli. The most conspicuous downstream effect of cell polarity is the polar transport of the phytohormone auxin, which is the only known hormone transported in a polar fashion in and out of cells by specialized exporters and importers. The biological processes behind the establishment of cell polarity are still unknown, and researchers have proposed several models that have been tested using computer simulations. The evolution of computer models has progressed in tandem with scientific discoveries, which have highlighted the importance of genetic, chemical, and mechanical input in determining cell polarity and regulating polarity-dependent processes such as anisotropic growth, protein subcellular localization, and the development of organ shapes. The purpose of this review is to provide a comprehensive overview of the current understanding of computer models of cell polarity establishment in plants, focusing on the molecular and cellular mechanisms, the proteins involved, and the current state of the field.
Topics: Cell Polarity; Plants; Plant Growth Regulators; Indoleacetic Acids; Computer Simulation; Arabidopsis Proteins
PubMed: 37144853
DOI: 10.1093/plphys/kiad264