Macrophage Metabolic Reprogramming Emerges as a Key Driver of Chronic Transplant Rejection and a New Therapeutic Target
核心洞察
A comprehensive review published in Frontiers in Cellular and Infection Microbiology (搜索) details how macrophage metabolic reprogramming orchestrates ischemia-reperfusion injury (搜索), allograft rejection, and chronic graft dysfunction.
Pro-inflammatory M1 macrophages rely on aerobic glycolysis, while anti-inflammatory M2 macrophages depend on oxidative phosphorylation and fatty acid oxidation, with this metabolic plasticity governing transplant outcomes.
Preclinical strategies targeting macrophage metabolism—including 2-deoxyglucose, etomoxir, trametinib, and CRISPR/Cas9 gene editing—have significantly prolonged graft survival in animal models.
A comprehensive review published in Frontiers in Cellular and Infection Microbiology (搜索) systematically examines how macrophage metabolic reprogramming governs transplant outcomes, positioning these innate immune cells as central orchestrators of both short- and long-term graft survival. The review, authored by Chen, Kong, Nian, Wang, and Zheng (2026), synthesizes evidence that macrophage metabolic plasticity—rather than T cell-mediated immunity alone—represents a critical and underexploited therapeutic axis in organ transplantation.
Organ transplantation remains the definitive treatment for end-stage organ failure, yet long-term graft survival continues to be substantially limited by ischemia-reperfusion injury (搜索) (IRI), allograft rejection, and chronic graft dysfunction. The authors note that innate immune cells account for approximately 38–60% of allograft-infiltrating leukocytes, with macrophages playing a pivotal role in regulating post-transplant immune responses. Current immunosuppressive regimens, they argue, have not fully exploited the metabolic plasticity of these cells.
The Metabolic Basis of Macrophage Polarization
Macrophages display remarkable functional plasticity, classically defined by pro-inflammatory (M1) and anti-inflammatory (M2) polarization states. This dual capacity is governed by dynamic metabolic reprogramming orchestrated by key metabolic nodes. M1 macrophages rely primarily on aerobic glycolysis and secrete pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, whereas M2 macrophages depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to sustain anti-inflammatory and tissue-repair programs.
The review details the specific enzymes driving these divergent metabolic programs. Pyruvate kinase M2 (搜索) (PKM2), a key glycolytic enzyme, promotes M1 polarization via glycolytic reprogramming and HIF-1α (搜索)-dependent inflammatory gene transcription. Conversely, carnitine palmitoyltransferase 1A (搜索) (CPT1A), a rate-limiting enzyme in FAO, supports M2 polarization through FAO-driven OXPHOS. Core metabolic pathways encompass carbohydrate metabolism—glycolysis, the tricarboxylic acid (TCA) cycle, and the pentose phosphate pathway—alongside FAO and amino acid catabolism.
These pathways are dynamically modulated by microenvironmental cues such as hypoxia, lactate, and succinate, which in turn dictate macrophage phenotypic identity and effector function. The authors emphasize that macrophage metabolism does not operate as a simple binary switch: even M1-polarized cells can retain some OXPHOS capacity depending on the intensity of the activating stimulus and the surrounding tissue microenvironment.
Metabolic Reprogramming Across the Transplant Timeline
The review traces macrophage metabolic reprogramming from early IRI through acute rejection to chronic rejection, fibrosis, and post-transplant tumor recurrence. During IRI, the hypoxic microenvironment and damage-associated molecular patterns (DAMPs) released from injured graft tissues drive macrophage polarization toward the M1 phenotype, characterized by markedly enhanced glycolytic flux and activation of the MEK/ERK-PKM2 signaling axis.
Succinate plays a central mechanistic role in IRI. During ischemia, obstruction of the TCA cycle causes substantial succinate accumulation; upon reperfusion, this accrued succinate is rapidly reoxidized by succinate dehydrogenase, driving reverse electron transport at mitochondrial complex I and triggering a robust burst of reactive oxygen species (ROS).
During acute allograft rejection, tissue-resident macrophages are progressively supplanted by glycolysis-dominant M1 macrophages, which release pro-inflammatory cytokines and upregulate endothelial adhesion molecules such as VCAM-1, promoting T cell infiltration into the graft. In chronic rejection, M2 macrophages preferentially utilize OXPHOS to sustain secretion of transforming growth factor beta (TGF-β), promoting fibrosis and vascular remodeling—pathological features that distinguish chronic rejection from acute inflammatory injury.
The authors highlight that in human renal allograft biopsy samples collected one-year post-transplant, M2-activated macrophages have been found to constitute up to 92% of all infiltrating macrophages. Macrophage-to-myofibroblast transition (MMT) represents another critical cellular pathway in graft fibrosis, with methyltransferase 3 (METTL3) enhancing M2-to-MMT transition via the TGF-β1/Smad3 signaling axis.
Emerging Therapeutic Strategies
The review catalogs a range of preclinical interventions targeting macrophage metabolism. Small-molecule metabolic inhibitors include 2-deoxyglucose (2-DG), a structural glucose analogue that competitively inhibits hexokinase and significantly prevents chronic lung allograft dysfunction in a mouse lung transplantation model. Etomoxir, an irreversible CPT1A inhibitor, blocks FAO and prolongs median heart allograft survival from 8 to 13 days in murine models. Trametinib, a selective MEK1/2 inhibitor, ameliorates chronic heart transplant rejection by blocking PKM2 nuclear translocation, prolonging median graft survival from 55 to 85 days.
Nanoparticle and gene-editing platforms have also shown promise. A high-density lipoprotein (HDL) nanocarrier targeting the mTOR pathway in macrophages prolonged median graft survival from 7 to more than 100 days in a mouse heart transplant model. Macrophage-specific Mek1/2 knockout mice generated by CRISPR/Cas9 gene editing exhibited markedly reduced pro-inflammatory phenotype and glycolytic capacity, and were significantly protected against chronic cardiac allograft rejection, prolonging median graft survival from 55 to more than 100 days. Myeloid-specific Setdb1 knockout blocked epigenetic reprogramming of profibrotic macrophages, prolonging median graft survival from 80 to more than 150 days.
Cell-based therapies have also been explored. Mesenchymal stem cell-derived exosomes carrying soluble Fgl2 reprogram macrophages toward an M2 anti-inflammatory phenotype, prolonging median graft survival from 7 to 23 days in a murine cardiac transplantation model. Erythropoietin was found to counteract trained immunity by reversing metabolic and epigenetic alterations, prolonging median graft survival from 35 to more than 100 days.
Challenges to Clinical Translation
The authors identify several critical challenges that must be addressed before clinical translation becomes feasible. A major challenge lies in the metabolic interdependence of multiple leukocyte and parenchymal cell subsets, meaning metabolic changes observed in bulk allograft tissue may not reflect macrophage-intrinsic alterations.
Target specificity is a primary concern. Conventional metabolic drugs may non-selectively impair the function of other immune cell populations, including T cells and dendritic cells. The authors note that FAO is also an important metabolic pathway of regulatory T (Treg) cells, which are highly dependent on FAO-driven OXPHOS for their suppressive function—so targeting FAO alone may risk weakening Treg-mediated immune tolerance and aggravating graft rejection.
Phenotypic complexity presents another obstacle, as macrophage polarization along the M1/M2 spectrum is highly context-dependent, with intermediate phenotypic states (M2a, M2b, M2c) exhibiting overlapping metabolic signatures. Translational biomarkers also remain underdeveloped, with metabolic signatures such as PKM2 and iNOS holding promise as early diagnostic markers but lacking standardized detection platforms and clinically validated thresholds.
"Harnessing these metabolic nodes may complement current immunosuppression and improve graft survival, warranting future clinical evaluation," the authors conclude. They call for integration of multi-omic datasets—encompassing the metabolome, epigenome, transcriptome, and proteome—to construct precision treatment algorithms that account for individual metabolic heterogeneity, ultimately aiming to confer durable transplantation immune tolerance.