Beyond M1/M2 Dichotomy: Macrophage Immunometabolism Identified as Mechanism for Sequential Damage in Heart, Liver, and Kidney Complex Diseases
Background
As the prevalence of obesity and type 2 diabetes surges, there is an increasing number of patients with complex metabolic diseases characterized by simultaneous dysfunction of the heart, liver, and kidneys. In clinical practice, cases where Cardiovascular-Kidney-Metabolic (CKM) syndrome or metabolic dysfunction-associated steatohepatitis (MASH) rapidly progress to heart failure or end-stage renal disease are frequently observed.
A notable point is that the simultaneous damage to these three organs is not a simple complication resulting from independent occurrences. The traditional medical establishment has strictly divided specialties such as cardiology, hepatology, and nephrology, primarily tracking local lesions of each organ. Therapies targeting specific organs have been insufficient to block the spread of inflammation that triggers chain reactions in other organs. While chronic low-grade inflammation has been identified as the fundamental cause, the identity of the immunological mediators spreading inflammation across organs has long remained veiled. This is why there has been a persistent call to elucidate the cross-talk pathways of immune-metabolic signals exchanged among the three organs.
Key Findings
Researchers have identified macrophages as the key mediators driving tissue damage and interaction among the three metabolic organs—heart, liver, and kidney—and have comprehensively summarized the pathological mechanism from an immunometabolic perspective. The existing binary classification system that simply divides tissue macrophages into pro-inflammatory M1 and anti-inflammatory M2 is considered unable to fully capture the actual in vivo heterogeneity.
In metabolic disease lesions, glucolipotoxicity—the combination of hyperglycemia and dyslipidemia—directly disrupts the intracellular metabolic pathways of macrophages. When macrophages are exposed to excessive glucose and free fatty acids, the intracellular Sirtuin (SIRT) signaling pathway is inhibited, while abnormal hyperactivation of the NOD-like receptor protein 3 (NLRP3) inflammasome in the cytoplasm is induced. This metabolic imbalance promotes metabolic reprogramming that disrupts macrophage mitochondrial respiration, shifting them toward a pro-inflammatory phenotype.
A macrophage subpopulation expressing chemokine receptor 2 (CCR2) is cited as the central axis mediating the vicious cycle between organs. CCR2-positive macrophages, activated by inflammatory stimuli in liver lesions, released large amounts of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) into the bloodstream. The released cytokines travel through the blood vessels to infiltrate myocardial and renal tissues, stimulating local capillary endothelial cells and promoting infiltration. In cardiomyocytes, fibrosis and impaired relaxation functions follow, while in renal glomeruli, podocyte damage and proteinuria are triggered. The analysis suggests that the three organs do not fail independently, but rather undergo a simultaneous collapse in a networked manner due to signals transmitted by the immunometabolic reprogramming of macrophages.
Significance and Outlook
This analysis heralds a paradigm shift from the existing approach of treating the heart, liver, and kidney as individual disease units. As the dysregulation of macrophage immunometabolism has emerged as a common pathological engine for the three organs, a foothold has been established for discovering common targets capable of simultaneously controlling multi-organ damage. Multi-target strategies, such as using SIRT activators, NLRP3 inflammasome inhibitors, or CCR2 antagonists to break the inter-organ inflammatory chain, are cited as representative alternatives.
Challenges to clinical application remain significant. Macrophages in vivo naturally perform their inherent physiological functions of defending against infection and repairing damaged tissue. If pathogenic macrophage subpopulations cannot be selectively inhibited, there is a persistent risk of side effects such as systemic immune suppression or delayed tissue regeneration. It is time for the co-development of precision delivery technologies that can identify unique markers of target subpopulations by integrating single-cell transcriptomics and spatial biology techniques, and deliver drugs specifically to those cells.
This review examines metabolic comorbidities affecting the heart, liver and kidney. The clinical prevalence of cardiohepatorenal metabolic comorbidities associated with obesity and type 2 diabetes is substantial. Chronic low-grade inflammation serves as the fundamental pathogenic mechanism. Abnormal macrophage activation is associated with metabolic disorders and damage to multiple organs. The conventional M1/M2 binary classification fails to adequately capture the heterogeneity of macrophages in vivo. Previous studies have primarily focused on the investigation of individual organs, leaving the cross-organ immune-metabolic linkage mechanism poorly understood. Furthermore, targeted interventions often lack precision. In this study, we systematically summarize the roles of macrophage polarization, phenotypic remodeling and metabolic activation in the injury of three metabolic organs. We also analyze their mediating functions in inter-organ immune-metabolic crosstalk and the associated pathological connections. Glycolipid toxicity impairs the glycolipid metabolism of macrophages via the NLRP3/SIRT pathway, resulting in a pro-inflammatory polarization advantage. Specific subsets of macrophages, including CCR2
This research provides a concrete direction for the development of next-generation metabolic disease drugs and the design of clinical trials. Moving away from the existing practice of independently developing treatments for liver disease or heart failure, establishing a multi-organ combination drug pipeline that simultaneously targets inhibition of liver fibrosis and preservation of cardiac and renal function by regulating the macrophage SIRT/NLRP3 axis is emerging as a realistic alternative.
The potential for application in the clinical diagnostic field is also high. By tracking circulating CCR2-positive monocyte levels or macrophage-specific metabolic markers carried in exosomes using liquid biopsy technology, a customized monitoring system can be established to early identify high-risk groups among patients with metabolic disorders who are likely to develop fatal multi-organ complications such as myocardial infarction or chronic renal failure.