Atieh Raoufi, Hamed Soleimani Samarkhazan, Sina Nouri, Mohammad Navid Khaksari, Parvaneh Abbasi Sourki, Omolbanin Sargazi Aval, Behzad Baradaran, Mojtaba Aghaei
{"title":"Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets.","authors":"Atieh Raoufi, Hamed Soleimani Samarkhazan, Sina Nouri, Mohammad Navid Khaksari, Parvaneh Abbasi Sourki, Omolbanin Sargazi Aval, Behzad Baradaran, Mojtaba Aghaei","doi":"10.1007/s10238-025-01588-0","DOIUrl":null,"url":null,"abstract":"<p><p>Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"73"},"PeriodicalIF":3.2000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885342/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10238-025-01588-0","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.
期刊介绍:
Clinical and Experimental Medicine (CEM) is a multidisciplinary journal that aims to be a forum of scientific excellence and information exchange in relation to the basic and clinical features of the following fields: hematology, onco-hematology, oncology, virology, immunology, and rheumatology. The journal publishes reviews and editorials, experimental and preclinical studies, translational research, prospectively designed clinical trials, and epidemiological studies. Papers containing new clinical or experimental data that are likely to contribute to changes in clinical practice or the way in which a disease is thought about will be given priority due to their immediate importance. Case reports will be accepted on an exceptional basis only, and their submission is discouraged. The major criteria for publication are clarity, scientific soundness, and advances in knowledge. In compliance with the overwhelmingly prevailing request by the international scientific community, and with respect for eco-compatibility issues, CEM is now published exclusively online.