Review

Authors: Thomas A Wynn, Kevin M Vannella

Inflammatory monocytes and tissue-resident macrophages are key regulators of tissue repair, regeneration, and fibrosis. After tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contribute to a state of persistent injury, and this could lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue-regenerating phenotypes after injury, and we highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically.

Topics: Animals; Cell Communication; Cell Differentiation; Fibrosis; Humans; Macrophage Activation; Macrophages; Phenotype; Regeneration; Wound Healing

PubMed: 26982353
DOI: 10.1016/j.immuni.2016.02.015

Review

Authors: Suguru Kadomoto, Kouji Izumi, Atsushi Mizokami...

Macrophages are present in most human tissues and have very diverse functions. Activated macrophages are usually divided into two phenotypes, M1 macrophages and M2 macrophages, which are altered by various factors such as microorganisms, tissue microenvironment, and cytokine signals. Macrophage polarity is very important for infections, inflammatory diseases, and malignancies; its management can be key in the prevention and treatment of diseases. In this review, we assess the current state of knowledge on macrophage polarity and report on its prospects as a therapeutic target.

Topics: Animals; Cell Polarity; Cytokines; Disease; Humans; Macrophages

PubMed: 35008577
DOI: 10.3390/ijms23010144

Review

Authors: Martin Guilliams, Charlotte L Scott

Single-cell and spatial transcriptomic technologies have revealed an underappreciated heterogeneity of liver macrophages. This has led us to rethink the involvement of macrophages in liver homeostasis and disease. Identification of conserved gene signatures within these cells across species and diseases is enabling the correct identification of specific macrophage subsets and the generation of more specific tools to track and study the functions of these cells. Here, we discuss what is currently known about the definitions of these different macrophage populations, the markers that can be used to identify them, how they are wired within the liver, and their functional specializations in health and disease.

Topics: Homeostasis; Kupffer Cells; Liver; Macrophages; Transcriptome

PubMed: 36103850
DOI: 10.1016/j.immuni.2022.08.002

Review

Authors: Tomi Lazarov, Sergio Juarez-Carreño, Nehemiah Cox...

Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies.

Topics: Animals; Humans; Cell Differentiation; Cell Lineage; Hematopoietic Stem Cells; Macrophages; Microglia; Monocytes; Organ Specificity; Disease

PubMed: 37344646
DOI: 10.1038/s41586-023-06002-x

Review

Authors: Haotian Bo, Ulrich Aymard Ekomi Moure, Yuanmiao Yang...

(Mtb), the causative agent of Tuberculosis (TB), remains a pathogen of great interest on a global scale. This airborne pathogen affects the lungs, where it interacts with macrophages. Acidic pH, oxidative and nitrosative stressors, and food restrictions make the macrophage's internal milieu unfriendly to foreign bodies. Mtb subverts the host immune system and causes infection due to its genetic arsenal and secreted effector proteins. and research have examined Mtb-host macrophage interaction. This interaction is a crucial stage in Mtb infection because lung macrophages are the first immune cells Mtb encounters in the host. This review summarizes Mtb effectors that interact with macrophages. It also examines how macrophages control and eliminate Mtb and how Mtb manipulates macrophage defense mechanisms for its own survival. Understanding these mechanisms is crucial for TB prevention, diagnosis, and treatment.

Topics: Humans; Mycobacterium tuberculosis; Macrophages; Tuberculosis; Macrophages, Alveolar; Lung; Host-Pathogen Interactions

PubMed: 36936766
DOI: 10.3389/fcimb.2023.1062963

Review

Authors: Thomas A Wynn, Ajay Chawla, Jeffrey W Pollard...

Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

Topics: Animals; Cell Lineage; Disease; Fibrosis; Growth and Development; Homeostasis; Humans; Macrophages

PubMed: 23619691
DOI: 10.1038/nature12034

Review

Authors: Runkai Chen, Hongrui Zhang, Botao Tang...

The immune response holds a pivotal role in cardiovascular disease development. As multifunctional cells of the innate immune system, macrophages play an essential role in initial inflammatory response that occurs following cardiovascular injury, thereby inducing subsequent damage while also facilitating recovery. Meanwhile, the diverse phenotypes and phenotypic alterations of macrophages strongly associate with distinct types and severity of cardiovascular diseases, including coronary heart disease, valvular disease, myocarditis, cardiomyopathy, heart failure, atherosclerosis and aneurysm, which underscores the importance of investigating macrophage regulatory mechanisms within the context of specific diseases. Besides, recent strides in single-cell sequencing technologies have revealed macrophage heterogeneity, cell-cell interactions, and downstream mechanisms of therapeutic targets at a higher resolution, which brings new perspectives into macrophage-mediated mechanisms and potential therapeutic targets in cardiovascular diseases. Remarkably, myocardial fibrosis, a prevalent characteristic in most cardiac diseases, remains a formidable clinical challenge, necessitating a profound investigation into the impact of macrophages on myocardial fibrosis within the context of cardiac diseases. In this review, we systematically summarize the diverse phenotypic and functional plasticity of macrophages in regulatory mechanisms of cardiovascular diseases and unprecedented insights introduced by single-cell sequencing technologies, with a focus on different causes and characteristics of diseases, especially the relationship between inflammation and fibrosis in cardiac diseases (myocardial infarction, pressure overload, myocarditis, dilated cardiomyopathy, diabetic cardiomyopathy and cardiac aging) and the relationship between inflammation and vascular injury in vascular diseases (atherosclerosis and aneurysm). Finally, we also highlight the preclinical/clinical macrophage targeting strategies and translational implications.

Topics: Humans; Macrophages; Cardiovascular Diseases; Fibrosis; Inflammation; Animals

PubMed: 38816371
DOI: 10.1038/s41392-024-01840-1

Comparative Study

Authors: Pengfei Li, Zhifang Hao, Jingyu Wu...

Macrophages can be polarized into classically activated macrophages (M1) and alternatively activated macrophages (M2) in the immune system, performing pro-inflammatory and anti-inflammatory functions, respectively. Human THP-1 and mouse RAW264.7 cell line models have been widely used in various macrophage-associated studies, while the similarities and differences in protein expression profiles between the two macrophage models are still largely unclear. In this study, the protein expression profiles of M1 and M2 phenotypes from both THP-1 and RAW264.7 macrophages were systematically investigated using mass spectrometry-based proteomics. By quantitatively analyzing more than 5,000 proteins among different types of macrophages (M0, M1 and M2) from both cell lines, we identified a list of proteins that were uniquely up-regulated in each macrophage type and further confirmed 43 proteins that were commonly up-regulated in M1 macrophages of both cell lines. These results revealed considerable divergences of each polarization type between THP-1 and RAW264.7 macrophages. Moreover, the mRNA and protein expression of CMPK2, RSAD2, DDX58, and DHX58 were strongly up-regulated in M1 macrophages for both macrophage models. These data can serve as important resources for further studies of macrophage-associated diseases in experimental pathology using human and mouse cell line models.

Topics: Animals; Humans; Macrophage Activation; Macrophages; Mice; Proteomics; RAW 264.7 Cells; THP-1 Cells

PubMed: 34267761
DOI: 10.3389/fimmu.2021.700009

Review

Authors: Xian Zhang, Liangliang Ji, Ming O Li...

Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic transformation, most prevalently of epithelial cell lineages, results in maladaptation of resident tissue macrophage differentiation pathways to generate parenchymal and interstitial tumor-associated macrophages that largely foster cancer progression. In addition to growth factors, nutrients that can be consumed, stored, recycled, or converted to signaling molecules have emerged as crucial regulators of macrophage responses in tumor. Here, we review how nutrient acquisition through plasma membrane transporters and engulfment pathways control tumor-associated macrophage differentiation and function. We also discuss how nutrient metabolism regulates tumor-associated macrophages and how these processes may be targeted for cancer therapy.

Topics: Animals; Humans; Tumor-Associated Macrophages; Macrophages; Cell Differentiation; Neoplasms; Nutrients

PubMed: 36630912
DOI: 10.1016/j.immuni.2022.12.003

Review

Authors: Kaiyue Wu, Kangjia Lin, Xiaoyan Li...

The immunosuppressive status of the tumor microenvironment (TME) remains poorly defined due to a lack of understanding regarding the function of tumor-associated macrophages (TAMs), which are abundant in the TME. TAMs are crucial drivers of tumor progression, metastasis, and resistance to therapy. Intra- and inter-tumoral spatial heterogeneities are potential keys to understanding the relationships between subpopulations of TAMs and their functions. Antitumor M1-like and pro-tumor M2-like TAMs coexist within tumors, and the opposing effects of these M1/M2 subpopulations on tumors directly impact current strategies to improve antitumor immune responses. Recent studies have found significant differences among monocytes or macrophages from distinct tumors, and other investigations have explored the existence of diverse TAM subsets at the molecular level. In this review, we discuss emerging evidence highlighting the redefinition of TAM subpopulations and functions in the TME and the possibility of separating macrophage subsets with distinct functions into antitumor M1-like and pro-tumor M2-like TAMs during the development of tumors. Such redefinition may relate to the differential cellular origin and monocyte and macrophage plasticity or heterogeneity of TAMs, which all potentially impact macrophage biomarkers and our understanding of how the phenotypes of TAMs are dictated by their ontogeny, activation status, and localization. Therefore, the detailed landscape of TAMs must be deciphered with the integration of new technologies, such as multiplexed immunohistochemistry (mIHC), mass cytometry by time-of-flight (CyTOF), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and systems biology approaches, for analyses of the TME.

Topics: Animals; Cell Plasticity; Gene Expression Regulation, Neoplastic; Humans; Macrophages; Neoplasms; Phenotype; Signal Transduction; Transcriptome; Tumor Microenvironment

PubMed: 32849616
DOI: 10.3389/fimmu.2020.01731