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Notch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5.Nature Communications Sep 2023Hematopoietic progenitors are enriched in the endocardial cushion and contribute, in a Nkx2-5-dependent manner, to tissue macrophages required for the remodeling of...
Hematopoietic progenitors are enriched in the endocardial cushion and contribute, in a Nkx2-5-dependent manner, to tissue macrophages required for the remodeling of cardiac valves and septa. However, little is known about the molecular mechanism of endocardial-hematopoietic transition. In the current study, we identified the regulatory network of endocardial hematopoiesis. Signal network analysis from scRNA-seq datasets revealed that genes in Notch and retinoic acid (RA) signaling are significantly downregulated in Nkx2-5-null endocardial cells. In vivo and ex vivo analyses validate that the Nkx2-5-Notch axis is essential for the generation of both hemogenic and cushion endocardial cells, and the suppression of RA signaling via Dhrs3 expression plays important roles in further differentiation into macrophages. Genetic ablation study revealed that these macrophages are essential in cardiac valve remodeling. In summary, the study demonstrates that the Nkx2-5/Notch/RA signaling plays a pivotal role in macrophage differentiation from hematopoietic progenitors.
Topics: Endocardium; Macrophages; Histiocytes; Cell Differentiation; Tretinoin
PubMed: 37669937
DOI: 10.1038/s41467-023-41039-6 -
Journal of Neuroinflammation Nov 2023Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the...
BACKGROUND
Subarachnoid hemorrhage (SAH) is an uncommon type of potentially fatal stroke. The pathophysiological mechanisms of brain injury remain unclear, which hinders the development of drugs for SAH. We aimed to investigate the pathophysiological mechanisms of SAH and to elucidate the cellular and molecular biological response to SAH-induced injury.
METHODS
A cross-species (human and mouse) multiomics approach combining high-throughput data and bioinformatic analysis was used to explore the key pathophysiological processes and cells involved in SAH-induced brain injury. Patient data were collected from the hospital (n = 712). SAH was established in adult male mice via endovascular perforation, and flow cytometry, a bone marrow chimera model, qPCR, and microglial depletion experiments were conducted to explore the origin and chemotaxis mechanism of the immune cells. To investigate cell effects on SAH prognosis, murine neurological function was evaluated based on a modified Garcia score, pole test, and rotarod test.
RESULTS
The bioinformatics analysis confirmed that inflammatory and immune responses were the key pathophysiological processes after SAH. Significant increases in the monocyte levels were observed in both the mouse brains and the peripheral blood of patients after SAH. Ly6C-high monocytes originated in the bone marrow, and the skull bone marrow contribute a higher proportion of these monocytes than neutrophils. The mRNA level of Ccl2 was significantly upregulated after SAH and was greater in CD11b-positive than CD11b-negative cells. Microglial depletion, microglial inhibition, and CCL2 blockade reduced the numbers of Ly6C-high monocytes after SAH. With CCR2 antagonization, the neurological function of the mice exhibited a slow recovery. Three days post-SAH, the monocyte-derived dendritic cell (moDC) population had a higher proportion of TNF-α-positive cells and a lower proportion of IL-10-positive cells than the macrophage population. The ratio of moDCs to macrophages was higher on day 3 than on day 5 post-SAH.
CONCLUSIONS
Inflammatory and immune responses are significantly involved in SAH-induced brain injury. Ly6C-high monocytes derived from the bone marrow, including the skull bone marrow, infiltrated into mouse brains via CCL2 secreted from microglia. Moreover, Ly6C-high monocytes alleviated neurological dysfunction after SAH.
Topics: Humans; Mice; Male; Animals; Monocytes; Subarachnoid Hemorrhage; Brain Injuries; Macrophages; Stroke; Mice, Inbred C57BL
PubMed: 37978532
DOI: 10.1186/s12974-023-02939-y -
British Journal of Cancer Sep 2023This study aimed to investigate the expression and clinical significance of Dendritic cell-associated C-type lectin-1 (Dectin-1) in gastric cancer (GC), and to explore...
BACKGROUND
This study aimed to investigate the expression and clinical significance of Dendritic cell-associated C-type lectin-1 (Dectin-1) in gastric cancer (GC), and to explore the mechanism of Dectin-1 regulating tumour-associated macrophage (TAM)-mediated immune evasion in GC.
METHODS
The association of Dectin-1 cells with clinical outcomes was inspected by immunohistochemistry on tumour microarrays. Flow cytometry and RNA sequencing were applied to detect characteristics of T cells, phenotypic and transcriptional features of Dectin-1 TAMs. The effect of Dectin-1 blockade was evaluated using an in vitro intervention experiment based on fresh GC tissues.
RESULTS
High infiltration of intratumoral Dectin-1 cells predicted poor prognosis in GC patients. Dectin-1 cells were mainly composed of TAMs, and the accumulation of Dectin-1 TAMs was associated with T-cell dysfunction. Notably, Dectin-1 TAMs exhibited an immunosuppressive phenotype. Furthermore, blockade of Dectin-1 could reprogramme Dectin-1 TAMs and reactivate anti-tumour effects of T cells, as well as enhanced PD-1 inhibitor-mediated cytotoxicity of CD8 T cells against tumour cells.
CONCLUSIONS
Dectin-1 could affect T-cell anti-tumour immune response by regulating the immunosuppressive function of TAMs, leading to poor prognosis and immune evasion in GC patients. Blockade of Dectin-1 can be used alone or in combination with current therapeutic strategies in GC.
Topics: Humans; Tumor-Associated Macrophages; Stomach Neoplasms; CD8-Positive T-Lymphocytes; Macrophages; Lectins, C-Type; Tumor Microenvironment
PubMed: 37422529
DOI: 10.1038/s41416-023-02336-5 -
Frontiers in Immunology 2023Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens,... (Review)
Review
Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level.
Topics: Humans; Macrophages; Monocytes; Fibrosis; Inflammation; Atrophy
PubMed: 37868987
DOI: 10.3389/fimmu.2023.1194988 -
Redox Biology Aug 2023Reactive oxygen species (ROS) are a family of highly reactive molecules with numerous, often pleiotropic functions within the cell and the organism. Due to their... (Review)
Review
Reactive oxygen species (ROS) are a family of highly reactive molecules with numerous, often pleiotropic functions within the cell and the organism. Due to their potential to destroy biological structures such as membranes, enzymes and organelles, ROS have long been recognized as harmful yet unavoidable by-products of cellular metabolism leading to "oxidative stress" unless counterbalanced by cellular anti-oxidative defense mechanisms. Phagocytes utilize this destructive potential of ROS released in high amounts to defend against invading pathogens. In contrast, a regulated and fine-tuned release of "signaling ROS" (sROS) provides essential intracellular second messengers to modulate central aspects of immunity, including antigen presentation, activation of antigen presenting cells (APC) as well as the APC:T cell interaction during T cell activation. This regulated release of sROS is foremost attributed to the specialized enzyme NADPH-oxidase (NOX) 2 expressed mainly in myeloid cells such as neutrophils, macrophages and dendritic cells (DC). NOX-2-derived sROS are primarily involved in immune regulation and mediate protection against autoimmunity as well as maintenance of self-tolerance. Consequently, deficiencies in NOX2 not only result in primary immune-deficiencies such as Chronic Granulomatous Disease (CGD) but also lead to auto-inflammatory diseases and autoimmunity. A comprehensive understanding of NOX2 activation and regulation will be key for successful pharmaceutical interventions of such ROS-related diseases in the future. In this review, we summarize recent progress regarding immune regulation by NOX2-derived ROS and the consequences of its deregulation on the development of immune disorders.
Topics: Humans; Reactive Oxygen Species; NADPH Oxidases; Neutrophils; Granulomatous Disease, Chronic; Phagocytes
PubMed: 37379662
DOI: 10.1016/j.redox.2023.102795 -
Trends in Immunology Dec 2023Single-cell approaches have shone a spotlight on discrete context-specific tissue macrophage states, deconstructed to their most minute details. Machine-learning (ML)... (Review)
Review
Single-cell approaches have shone a spotlight on discrete context-specific tissue macrophage states, deconstructed to their most minute details. Machine-learning (ML) approaches have recently challenged that dogma by revealing a context-agnostic continuum of states shared across tissues. Both approaches agree that 'brake' and 'accelerator' macrophage subpopulations must be balanced to achieve homeostasis. Both approaches also highlight the importance of ensemble fluidity as subpopulations switch between wide ranges of accelerator and brake phenotypes to mount the most optimal wholistic response to any threat. A full comprehension of the rules that govern these brake and accelerator states is a promising avenue because it can help formulate precise macrophage re-education therapeutic strategies that might selectively boost or suppress disease-associated states and phenotypes across various tissues.
Topics: Humans; Macrophages
PubMed: 37945504
DOI: 10.1016/j.it.2023.10.006 -
Biomedicine & Pharmacotherapy =... Oct 2023Tumor-associated macrophages (TAMs) are the most critical effector cells of innate immunity and the most abundant tumor-infiltrating immune cells. They play a key role... (Review)
Review
Tumor-associated macrophages (TAMs) are the most critical effector cells of innate immunity and the most abundant tumor-infiltrating immune cells. They play a key role in the clearance of apoptotic bodies, regulation of inflammation, and tissue repair to maintain homeostasis in vivo. With the progression of triple-negative breast cancer(TNBC), TAMs are "subverted" from tumor-promoting immune cells to tumor-promoting immune suppressor cells, which play a significant role in tumor development and are considered potential targets for cancer therapy. Here, we explored how macrophages, as the most important part of the TNBC ecosystem, are "subverted" to drive cancer evolution and the uniqueness of TAMs in TNBC progression and metastasis. Similarly, we discuss the rationale and available evidence for TAMs as potential targets for TNBC therapy.
Topics: Humans; Triple Negative Breast Neoplasms; Ecosystem; Macrophages; Tumor-Associated Macrophages; Immunity, Innate
PubMed: 37660651
DOI: 10.1016/j.biopha.2023.115414 -
Frontiers in Immunology 2023Skeletal muscle is essential for body physical activity, energy metabolism, and temperature maintenance. It has excellent capabilities to maintain homeostasis and to... (Review)
Review
Skeletal muscle is essential for body physical activity, energy metabolism, and temperature maintenance. It has excellent capabilities to maintain homeostasis and to regenerate after injury, which indispensably relies on muscle stem cells, satellite cells (MuSCs). The quiescence, activation, and differentiation of MuSCs are tightly regulated in homeostatic and regenerating muscles. Among the important regulators are intramuscular macrophages, which are functionally heterogeneous with different subtypes present in a spatiotemporal manner to regulate the balance of different MuSC statuses. During chronic injury and aging, intramuscular macrophages often undergo aberrant activation, which in turn disrupts muscle homeostasis and regenerative repair. Growing evidence suggests that the aberrant activation is mainly triggered by altered muscle microenvironment. The trained immunity that affects myeloid progenitors during hematopoiesis may also contribute. Aged immune system may contribute, in part, to the aging-related sarcopenia and compromised skeletal muscle injury repair. As macrophages are actively involved in the progression of many muscle diseases, manipulating their functional activation has become a promising therapeutic approach, which requires comprehensive knowledge of the cellular and molecular mechanisms underlying the diverse activation. To this end, we discuss here the current knowledge of multifaceted role of macrophages in skeletal muscle homeostasis, injury, and repair.
Topics: Muscle, Skeletal; Cell Differentiation; Macrophages; Homeostasis
PubMed: 37954602
DOI: 10.3389/fimmu.2023.1274816 -
Cancer Immunology, Immunotherapy : CII Dec 2023Macrophages are important precursor cell types of the innate immune system and bridge adaptive immune responses through the antigen presentation system. Meanwhile,... (Review)
Review
Macrophages are important precursor cell types of the innate immune system and bridge adaptive immune responses through the antigen presentation system. Meanwhile, macrophages constitute substantial portion of the stromal cells in the tumor microenvironment (TME) (referred to as tumor-associated macrophages, or TAMs) and exhibit conflicting roles in the development, invasion, and metastasis of thyroid cancer (TC). Moreover, TAMs play a crucial role to the behavior of TC due to their high degree of infiltration and prognostic relevance. Generally, TAMs can be divided into two subgroups; M1-like TAMs are capable of directly kill tumor cells, and recruiting and activating other immune cells in the early stages of cancer. However, due to changes in the TME, M2-like TAMs gradually increase and promote tumor progression. This review aims to discuss the impact of TAMs on TC, including their role in tumor promotion, gene mutation, and other factors related to the polarization of TAMs. Finally, we will explore the M2-like TAM-centered therapeutic strategies, including chemotherapy, clinical trials, and combinatorial immunotherapy.
Topics: Humans; Tumor-Associated Macrophages; Thyroid Neoplasms; Prognosis; Macrophages; Immunotherapy; Tumor Microenvironment
PubMed: 37796300
DOI: 10.1007/s00262-023-03549-6 -
Cell Communication and Signaling : CCS Aug 2023Macrophages are immune cells with high plasticity that are widely distributed in all tissues and organs of the body. Under the influence of the immune microenvironment... (Review)
Review
Macrophages are immune cells with high plasticity that are widely distributed in all tissues and organs of the body. Under the influence of the immune microenvironment of breast tumors, macrophages differentiate into various germline lineages. They exert pro-tumor or tumor-suppressive effects by secreting various cytokines. Pyroptosis is mediated by Gasdermin family proteins, which form holes in cell membranes and cause a violent inflammatory response and cell death. This is an important way for the body to fight off infections. Tumor cell pyroptosis can activate anti-tumor immunity and inhibit tumor growth. At the same time, it releases inflammatory mediators and recruits tumor-associated macrophages (TAMs) for accumulation. Macrophages act as "mediators" of cytokine interactions and indirectly influence the pyroptosis pathway. This paper describes the mechanism of action on the part of TAM in affecting the pyroptosis process of breast tumor cells, as well as its key role in the tumor microenvironment. Additionally, it provides the basis for in-depth research on how to use immune cells to affect breast tumors and guide anti-tumor trends, with important implications for the prevention and treatment of breast tumors. Video Abstract.
Topics: Humans; Female; Pyroptosis; Tumor-Associated Macrophages; Breast Neoplasms; Macrophages; Cytokines; Tumor Microenvironment
PubMed: 37542283
DOI: 10.1186/s12964-023-01208-y