Macrophage surface protein Mac-2 mediates inflammatory and stromal stress pathways in doxorubicin-induced cardiac injury
Year: 2026
Type: article
Abstract: BACKGROUND: Doxorubicin (DOX) cardiotoxicity is a major complication of cancer therapy and involves macrophage-driven inflammation and myocardial remodeling. The macrophage surface protein Mac-2 (galectin-3) is upregulated in cardiac injury, but its role in regulating macrophage function and downstream injury pathways remains undefined. METHODS: We used CRISPR/Cas9-engineered Mac-2-null macrophages to evaluate chemotaxis, cytokine gene expression, and lysosomal stress signaling in vitro. To examine paracrine injury mechanisms, we performed co-culture assays with cardiomyocytes and fibroblasts. In vivo, we studied homozygous Mac-2-mutant mice and used CD45.1/CD45.2 bone marrow transplantation with lineage tracking to define hematopoietic versus stromal contributions to DOX-induced inflammation, apoptosis, fibrosis, and systolic dysfunction. RESULTS: Doxorubicin induced Mac-2 and inflammatory transcripts (Il6, Tnf, Ccl2) in wild-type macrophages, whereas Mac-2 knockout reduced DOX uptake, chemotaxis, and cytokine induction. In co-culture, DOX-treated WT macrophages increased caspase-3/7 activity in cardiomyocytes and phospho-TFEB in fibroblasts, both attenuated with Mac-2 deletion. In vivo, Mac-2-null mice exhibited less cardiac inflammation, apoptosis, and fibrosis with preserved systolic function and reduced mortality. Bone marrow transplantation demonstrated that hematopoietic Mac-2 suppressed cardiac Tfeb and upregulated Sqstm1 and Tgfb1, enhancing inflammatory and apoptotic responses, whereas Mac-2-deficient marrow restored Tfeb, limited Sqstm1/Tgfb1, and protected cardiac function. CONCLUSIONS: Mac-2 promotes DOX-induced cardiac injury by facilitating inflammatory activation in macrophages, driving fibroblast lysosomal stress via TFEB and SQSTM1, and augmenting caspase-3–associated apoptosis in cardiomyocytes. Loss of Mac-2 in hematopoietic cells reduces inflammation, fibrosis, and systolic dysfunction in vivo.
Source: Cardio-Oncology
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,790
Awards: Pediatric Cardiomyopathy Registry, Training Program in Cardiovascular Signaling, Genetic Mechanisms of Anthracycline Cardiotoxicity in Pediatric Cancer Survivors, Atherosclerotic Risk and Response to Exercise Intervention in HIV+ Children, Cardiovascular Status of HAART-Exposed Infants/Children, Pediatric Cardiomyopathy Specimen Repository, Pediatric HIV/AIDS Cohort Study (PHACS) Coordinating Center (CC) (U01), Therapeutic Index of Acute Lymphoblastic Leukemia, HAART Associated Cardiotoxicity in HIV-Infected Children, Primary Cardiomyopathies in Children: Research Directions & Strategies, Women and Infants Transmission Study IV, Baseline Predictors of Outcomes of Pediatric Dilated Cardiomyopathy, Cardiac Biomarkers in Pediatric Cardiomyopathy, Genotype-Phenotype Associations in Pediatric Cardiomyopathy, Pediatric HIV/AIDS Cohort Study (PHACS): Data and Operations Center (DOC)., FELLOWSHIP IN CLINICAL RESEARCH, Early Detection and Immunomodulation of PD-1 Inhibitor Induced Cardiotoxicity, University of Buffalo Clinical and Translational Science Institute, G8478173224, G9000184864, Roswell Park Cancer Center Support Grant, Immunomodulation of Galectin-3 to Prevent Radiation-Induced Myocardial Fibrogenesis, Inhibition of Radiation-Induced Coronary Microvascular Disease
OpenAlex ID: W7125402873