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Cellular & Molecular Immunology Sep 2023Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In both primary tumors and metastases, such... (Review)
Review
Macrophages are critical regulators of tissue homeostasis but are also abundant in the tumor microenvironment (TME). In both primary tumors and metastases, such tumor-associated macrophages (TAMs) seem to support tumor development. While we know that TAMs are the dominant immune cells in the TME, their vast heterogeneity and associated functions are only just being unraveled. In this review, we outline the various known TAM populations found thus far and delineate their specialized roles associated with the main stages of cancer progression. We discuss how macrophages may prime the premetastatic niche to enable the growth of a metastasis and then how subsequent metastasis-associated macrophages can support secondary tumor growth. Finally, we speculate on the challenges that remain to be overcome in TAM research.
Topics: Humans; Neoplasms; Macrophages; Tumor-Associated Macrophages; Tumor Microenvironment
PubMed: 37429944
DOI: 10.1038/s41423-023-01061-6 -
Hepatology (Baltimore, Md.) Mar 2024Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly...
BACKGROUND AND AIMS
Immune cells play a crucial role in liver aging. However, the impact of dynamic changes in the local immune microenvironment on age-related liver injury remains poorly understood. We aimed to characterize intrahepatic immune cells at different ages to investigate key mechanisms associated with liver aging.
APPROACH AND RESULTS
We carried out single-cell RNA sequencing on mouse liver tissues at 4 different ages, namely, the newborn, suckling, young, and aged stages. The transcriptomic landscape, cellular classification, and intercellular communication were analyzed. We confirmed the findings by multiplex immunofluorescence staining, flow cytometry, in vitro functional experiments, and chimeric animal models. Nine subsets of 89,542 immune cells with unique properties were identified, of which Cxcl2+ macrophages within the monocyte/macrophage subset were preferentially enriched in the aged liver. Cxcl2+ macrophages presented a senescence-associated secretory phenotype and recruited neutrophils to the aged liver through the CXCL2-CXCR2 axis. Through the secretion of IL-1β and TNF-α, Cxcl2+ macrophages stimulated neutrophil extracellular traps formation. Targeting the CXCL2-CXCR2 axis limited the neutrophils migration toward the liver and attenuated age-related liver injury. Moreover, the relationship between Cxcl2+ macrophages and neutrophils in age-related liver injury was further validated by human liver transplantation samples.
CONCLUSIONS
This in-depth study illustrates that the mechanism of Cxcl2+ macrophage-driven neutrophil activation involves the CXCL2-CXCR2 axis and provides a potential therapeutic strategy for age-related liver injury.
Topics: Mice; Animals; Infant, Newborn; Humans; Aged; Neutrophils; Chemokine CXCL2; Liver; Macrophages; Aging
PubMed: 37695548
DOI: 10.1097/HEP.0000000000000590 -
Methods in Molecular Biology (Clifton,... 2024One hundred years have passed since the death of Élie Metchnikoff (1845-1916). He was the first to observe the uptake of particles by cells and realized the importance... (Review)
Review
One hundred years have passed since the death of Élie Metchnikoff (1845-1916). He was the first to observe the uptake of particles by cells and realized the importance of this process, named phagocytosis, for the host response to injury and infection. He also was a strong advocate of the role of phagocytosis in cellular immunity, and with this, he gave us the basis for our modern understanding of inflammation and the innate immune response. Phagocytosis is an elegant but complex process for the ingestion and elimination of pathogens, but it is also important for the elimination of apoptotic cells and hence fundamental for tissue homeostasis. Phagocytosis can be divided into four main steps: (i) recognition of the target particle, (ii) signaling to activate the internalization machinery, (iii) phagosome formation, and (iv) phagolysosome maturation. In this chapter, we present a general view of our current knowledge on phagocytosis performed mainly by professional phagocytes through antibody and complement receptors and discuss aspects that remain incompletely understood.
Topics: Phagocytosis; Humans; Animals; Phagosomes; Phagocytes; Signal Transduction; Immunity, Innate
PubMed: 38888769
DOI: 10.1007/978-1-0716-3890-3_3 -
Current Opinion in Immunology Oct 2023Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages... (Review)
Review
Macrophages are phagocytic cells distributed across tissues that sustain homeostasis by constantly probing their local environment. Upon perturbations, macrophages rewire their energy metabolism to execute their immune programs. Intensive research in the field of immunometabolism highlights cell-intrinsic immunometabolites such as succinate and itaconate as immunomodulatory signals. A role for cell-extrinsic stimuli now emerges with evidence for signals that shape macrophages' metabolism in a tissue-specific manner. In this review, we will cover macrophage immunometabolism in the gut, a complex metabolic and immunologically active tissue. During homeostasis, gut macrophages are constantly exposed to pro-inflammatory ligands from the microbiota, and in contrast, are balanced by microbiota-derived anti-inflammatory metabolites. Given their extensive metabolic changes during activation, spatial analyses of the tissue will allow the characterization of metabolic niches of macrophage in the gut. Identifying metabolic perturbations of macrophage subsets during chronic inflammation and infection can direct future tissue-specific metabolotherapies.
Topics: Humans; Macrophages; Energy Metabolism; Succinic Acid; Immunity; Inflammation
PubMed: 37473458
DOI: 10.1016/j.coi.2023.102369 -
Journal of Hepatology Oct 2023Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are...
BACKGROUND & AIMS
Ductular reaction expansion is associated with poor prognosis in patients with advanced liver disease. However, the mechanisms promoting biliary cell proliferation are largely unknown. Here, we identify neutrophils as drivers of biliary cell proliferation and the defective wound-healing response.
METHODS
The intrahepatic localization of neutrophils was evaluated in patients with chronic liver disease. Neutrophil dynamics were analyzed by intravital microscopy and neutrophil-labeling assays in DDC-treated mice. Neutrophil depletion or inhibition of recruitment was achieved using a Ly6g antibody or a CXCR1/2 inhibitor, respectively. Mice deficient in PAD4 (peptidyl arginine deiminase 4) and ELANE/NE (neutrophil elastase) were used to investigate the mechanisms underlying ductular reaction expansion.
RESULTS
In this study we describe a population of ductular reaction-associated neutrophils (DRANs), which are in direct contact with biliary epithelial cells in chronic liver diseases and whose numbers increased in parallel with disease progression. We show that DRANs are immobilized at the site of ductular reaction for a prolonged period of time. In addition, liver neutrophils display a unique phenotypic and transcriptomic profile, showing a decreased phagocytic capacity and increased oxidative burst. Depletion of neutrophils or inhibition of their recruitment reduces DRANs and the expansion of ductular reaction, while mitigating liver fibrosis and angiogenesis. Mechanistically, neutrophils deficient in PAD4 and ELANE abrogate neutrophil-induced biliary cell proliferation, thus indicating the role of neutrophil extracellular traps and elastase release in ductular reaction expansion.
CONCLUSIONS
Overall, our study reveals the accumulation of DRANs as a hallmark of advanced liver disease and a potential therapeutic target to mitigate ductular reaction and the maladaptive wound-healing response.
IMPACT AND IMPLICATIONS
Our results indicate that neutrophils are highly plastic and can have an extended lifespan. Moreover, we identify a new role of neutrophils as triggers of expansion of the biliary epithelium. Overall, the results of this study indicate that ductular reaction-associated neutrophils (or DRANs) are new players in the maladaptive tissue-healing response in chronic liver injury and may be a potential target for therapeutic interventions to reduce ductular reaction expansion and promote tissue repair in advanced liver disease.
Topics: Animals; Mice; Neutrophils; Liver; Liver Diseases; Cell Proliferation; Epithelium
PubMed: 37348790
DOI: 10.1016/j.jhep.2023.05.045 -
International Journal of Molecular... Oct 2023Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells... (Review)
Review
Cells are the smallest units that make up living organisms, which constantly undergo the processes of proliferation, differentiation, senescence and death. Dead cells need to be removed in time to maintain the homeostasis of the organism and keep it healthy. This process is called efferocytosis. If the process fails, this may cause different types of diseases. More and more evidence suggests that a faulty efferocytosis process is closely related to the pathological processes of respiratory diseases. In this review, we will first introduce the process and the related mechanisms of efferocytosis of the macrophage. Secondly, we will propose some methods that can regulate the function of efferocytosis at different stages of the process. Next, we will discuss the role of efferocytosis in different lung diseases and the related treatment approaches. Finally, we will summarize the drugs that have been applied in clinical practice that can act upon efferocytosis, in order to provide new ideas for the treatment of lung diseases.
Topics: Humans; Apoptosis; Phagocytosis; Macrophages; Phagocytes; Lung Diseases; Respiration Disorders
PubMed: 37834319
DOI: 10.3390/ijms241914871 -
The Journal of Experimental Medicine Feb 2024Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of...
Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not 30 wk after discontinuation, and reaccumulation of plaques coincided with loss of the microglial aducanumab signature and failure of microglia to reactivate. This suggests that despite the initial benefit from treatment, microglia are unable to respond later to restrain plaque reaccumulation, making further studies on the effect of amyloid-directed immunotherapy withdrawal crucial for assessing long-term safety and efficacy.
Topics: Animals; Mice; Microglia; Antibodies, Monoclonal, Humanized; Immunotherapy; Phagocytes; Plaque, Amyloid
PubMed: 38226975
DOI: 10.1084/jem.20231363 -
Cell Reports Jul 2023Kaposi's sarcoma herpesvirus (KSHV) establishes lifelong infection and persists in latently infected B cells. Paradoxically, in vitro B cell infection is inefficient,...
Kaposi's sarcoma herpesvirus (KSHV) establishes lifelong infection and persists in latently infected B cells. Paradoxically, in vitro B cell infection is inefficient, and cells rapidly die, suggesting the absence of necessary factor(s). KSHV epidemiology unexpectedly mirrors that of malaria and certain helminthic infections, while other herpesviruses are ubiquitous. Elevated circulating monocytes are common in these parasitic infections. Here, we show that KSHV infection of monocytes or M-CSF-differentiated (M2) macrophages is highly efficient. Proteomic analyses demonstrate that infection induces macrophage production of B cell chemoattractants and activating factor. We find that KSHV acts with monocytes or M2 macrophages to stimulate B cell survival, proliferation, and plasmablast differentiation. Further, macrophages drive infected plasma cell differentiation and long-term viral latency. In Kenya, where KSHV is endemic, we find elevated monocyte levels in children with malaria. These findings demonstrate a role for mononuclear phagocytes in KSHV B cell latency and suggest that mononuclear phagocyte abundance may underlie KSHV's geographic disparity.
Topics: Child; Humans; Herpesvirus 8, Human; Proteomics; B-Lymphocytes; Macrophages; Monocytes; Virus Latency
PubMed: 37440412
DOI: 10.1016/j.celrep.2023.112767 -
Trends in Immunology Dec 2023When recruited to mammalian tissues, monocytes differentiate into macrophages or dendritic cells (DCs). In the past few years, the existence of monocyte-derived DCs... (Review)
Review
When recruited to mammalian tissues, monocytes differentiate into macrophages or dendritic cells (DCs). In the past few years, the existence of monocyte-derived DCs (moDCs) was questioned by the discovery of new DC populations with overlapping phenotypes. Here, we critically review the evidence for monocyte differentiation into DCs in tissues and highlight their specific functions. Recent studies have shown that monocyte-derived macrophages (moMacs) with distinct life cycles coexist in tissues, both at steady state and upon inflammation. Integrating studies in mice and humans, we highlight specific features of moMacs during inflammation and tissue repair. We also discuss the notion of monocyte differentiation occurring via a binary fate decision. Deciphering monocyte-derived cell properties is essential for understanding their role in nonresolving inflammation and how they might be targeted for therapies.
Topics: Humans; Animals; Mice; Monocytes; Cell Differentiation; Dendritic Cells; Macrophages; Inflammation; Mammals
PubMed: 37949783
DOI: 10.1016/j.it.2023.10.005 -
Nature Immunology Dec 2023Cancer cells often overexpress CD47, which triggers the inhibitory receptor SIRPα expressed on macrophages, to elude phagocytosis and antitumor immunity....
Cancer cells often overexpress CD47, which triggers the inhibitory receptor SIRPα expressed on macrophages, to elude phagocytosis and antitumor immunity. Pharmacological blockade of CD47 or SIRPα is showing promise as anticancer therapy, although CD47 blockade has been associated with hematological toxicities that may reflect its broad expression pattern on normal cells. Here we found that, in addition to triggering SIRPα, CD47 suppressed phagocytosis by a SIRPα-independent mechanism. This mechanism prevented phagocytosis initiated by the pro-phagocytic ligand, SLAMF7, on tumor cells, due to a cis interaction between CD47 and SLAMF7. The CD47-SLAMF7 interaction was disrupted by CD47 blockade and by a first-in-class agonist SLAMF7 antibody, but not by SIRPα blockade, thereby promoting antitumor immunity. Hence, CD47 suppresses phagocytosis not only by engaging SIRPα, but also by masking cell-intrinsic pro-phagocytic ligands on tumor cells and knowledge of this mechanism may influence the decision between CD47 blockade or SIRPα blockade for therapeutic purposes.
Topics: Humans; Antigens, Differentiation; CD47 Antigen; Ligands; Macrophages; Neoplasms; Phagocytosis; Tumor Escape; Animals; Mice
PubMed: 37945822
DOI: 10.1038/s41590-023-01671-2