MeSH terms provide the most accurate representation of the topic of the literature. This research concluded the topics and subject trends of exosomes from macrophages using high-frequency major MESH terms/MESH subheadings. Exosomes/metabolism, Macrophages/metabolism are the most popular MESH phrases. We evaluated the distribution characteristics of related literature with BICOMB software and refined 5 clusters (10 research hotspots) with biclustering analysis. Then we created coordinates for each category in the strategy map and utilized social network analysis to uncover knowledge structures.
In the past 11 years, research connected to exosomes from macrophages had been boomed. From the standpoint of journals, Frontiers in immunology, Scientific reports, and International journal of molecular sciences are the top three journals, which are anticipated to continue to publish high-quality related publications in the future. Authors such as Wang Y are particularly prolific authors in the discipline. In national statistics, the United States published the most papers, reaching 333. Other countries including the UK and the Netherlands are also productive(Fig. 1).
Clusters 0 and 4 are found in the first quadrant of the strategy map, signifying that these prominent issues are relatively mature and well researched (Fig. 2C). Modifying exosome surface characteristics such as anchored proteins (Bioengineered EVs) could decrease pro-inflammatory cytokine responses or regulate other physiological processes 10. Exosomes from macrophages reduce heat hyperalgesia in a mouse model of inflammatory pain, implying an immunoprotective signal against inflammation11.
In bone tissue, tissue-resident macrophages coexist alongside bone tissue cells altering bone metabolism. The activity of osteoclasts links to different diseases and signaling pathways, and mature osteoclasts (mOCs) can be created by stimulating bone marrow macrophages with receptor activator of nuclear factor-b ligand (RANKL) 12. Osteosarcoma cells release exosomal miR-501-3p, which can induce osteoclast formation via the PTEN/PI3K/Akt signaling pathway13.
Clusters 1 and 2 are in the third quadrant and represent less mature themes that will require additional research in the future.
The interplay of macrophages with the tumor microenvironment(TME) has gotten a lot of interest. EVs are one of the important components of communication between tumor cells or the microenvironment14, which can promote or suppress tumor development, invasion, and metastasis. The miRNAs or long non-coding RNAs contained in EVs can act as the mediator. Exosomes from retinoblastoma cells are capable of increasing levels of monocyte chemotactic protein 1 (C‑C motif chemokine ligand 2), as well as miR-92a, miR-20a, miR-129a, and miR-17 to mediate tumor progression15. THP-1-induced macrophage-derived exosomes could facilitate osteosarcoma cell progression by transmitting miR-29a to osteosarcoma cells16. Tumor-derived exosomes (TEXs) have been engineered to aid tumor evasion and promote the differentiation of macrophages to adjust the immune response. Known as tumor-associated macrophages (TAMs), M2 macrophages promote cancer progression and metastasis, while M1 macrophages produce cytokines such as interleukin-12 (IL-12) and inhibit tumor growth1. Exosome quantification is often based on protein content, fluorescent labeling approaches are more precise and offer the added benefit of following EVs in vivo17.
Exosomes influence macrophage activity, resulting in polarity shifts that make exosomes a target for immune modulation18. Neutrophil-derived exosomes regulate macrophage behavior, and macrophages no longer trigger fibroblast-like synoviocytes after intra-articular injection of neutrophil-derived exosomes. This may aid in the control of synovial inflammation19. Exosomes purified from community-associated methicillin-resistant S. aureus strains can be internalized by human macrophages, which promoting and caspase-1 activation20. Exosomes are cell-free fluid with immunomodulation and vaccination potential. The advantages of exosomes, on the other hand, are not absolute. Conforti discovered that IL-10 and tgf1 levels in T and B cells were much higher, but the human granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were significantly lower. In vitro, the effects of exosomes alone on T cell proliferation and antibody production were not significantly increased21. More prospective studies are required to assess exosome relative merits.
Exosome membranes can effectively shield their contents from destruction, and their immunogenicity is minimal due to the small number of membrane-bound proteins that can dodge immune reactions. They are great drug carriers with enormous potential as cell-free players in bone disorders, inflammatory management, targeted therapy, and other applications22. Exosomes from metastatic breast cancer 4t1 cells can influence hepatic macrophage function and potentially minimize the negative effects of chemotherapy drugs23. MSC exosomes can mediate and stimulate tissue healing, and express a variety of immunomodulatory rather than immunosuppressive factors24. Inflammation is a critical regulating point in disorders that influence bone metabolism, such as diabetes. Zhang25 found that exosomes produced from adipose-derived mesenchymal stem cells (AD-MSCs) may block osteoclast release of IL-1 and IL-18 and reverse bone loss in diabetic rats. This has the potential to be a cell-free treatment for diabetic bone loss. Osteopontin (OPN) is a protein that regulates bone remodeling and tissue debridement. Investing in exosome-based drug delivery systems in the future could be a viable therapeutic approach; however, additional study on its components and physiology is required to clarify the currently unknown mechanism.
Cluster 3 is a mature issue in the fourth quadrant with potentials. The phenotypic transition of macrophages is currently a popular issue. Changes in the milieu of disease-site resident macrophage subsets may limit subtype transition by reflecting changes in their unique microenvironment. To increase the roles of resident macrophages in tissues, researchers have used macrophage exosomes or other methods to promote phenotype switch. The composition and content of exosomes can be influenced by changes in macrophage activity. Exosome synthesis by monocytes and macrophages is increased by alcohol, and exosome communication between immune cells is affected26. Exosomes produced by phagocytes have been shown to improve M2 polarization in microglia and induce neuroprotection27. More research is needed to better understand how macrophage subtype and microenvironment influence disease development. Studies have shown that exosomes from mesenchymal stem cells improve myocardial damage after myocardial infarction by boosting the transition of macrophages to M2 polarity28. Exosomes released by bone marrow mesenchymal stem cells also helped animals with respiratory problems29.
According to the social network analysis results (Fig. 3), the mature topic "Macrophages/metabolism" at the network's core is the mature topic with the highest centrality value, the most links with surrounding terms, and the most influence on the network. The pink boxes on the edge represented new research hotspots, including Extracellular Vesicles/immunology; Exosomes/transplantation; Mesenchymal Stem Cells/cytology; Extracellular Vesicles/physiology; Exosomes/chemistry; Exosomes/physiology; Exosomes/immunology; Cell-Derived Microparticles/immunology.
This work uses objective bibliometric approaches to demonstrate subjects for scholars to investigate additionally, although there are still some limitations. First, we only selected the literature in the PubMed database; there may be differences in the other database. Second, the co-word analysis concentrates on high-frequency words while ignoring low-frequency words, which should be considered in future bibliometric studies for statistical purposes.