A call to redefine cardiovascular immunobiology around leukocyte plasticity

Is Inflammation Inherently Pathological?

Inflammation has long been perceived as a destructive process, synonymous with tissue injury and disease. In the cardiovascular system, this has shaped our understanding of atherosclerosis, myocardial infarction, and heart failure. Yet, inflammation is fundamentally an adaptive, highly regulated biological response essential for maintaining homeostasis and initiating post-injury repair (1). The notion that inflammation is exclusively pathological has obscured its regenerative potential. Mounting evidence suggests that leukocyte-mediated signaling is not solely a driver of cardiac damage but also a prerequisite for effective healing and cardiac remodeling (2).

This evolving outlook reframes inflammation as a continuum of responses, ranging from acute defensive activation to coordinated resolution and regeneration. Rather than a binary state of “inflammatory versus anti-inflammatory,” inflammation unfolds along temporal and spatial gradients, with timing, cellular localization, and immune cell metabolism dictating outcomes favoring repair or chronic dysfunction (3). Leukocyte activity is not just a marker of pathology, but a manifestation of the heart’s attempt to restore equilibrium (4).

Here, we posit that inflammation itself is not pathological, but that cardiovascular disease instead arises from a failure of leukocyte plasticity. This is the capacity of immune cells to transition between functional states, reposition within microanatomical niches, and reprogram their metabolism to meet tissue demand. Leukocytes that arrive prepared to clear debris but never exit that state, fail to switch metabolic states (5) remain confined to inflammatory hotspots without migrating to reparative microenvironments (6). This concept is lineage-specific and most clearly illustrated by monocyte-derived macrophages transitioning from inflammatory, glycolytic, phagocytic states toward oxidative, pro-resolving, and pro-angiogenic phenotypes (7). Neutrophils similarly exhibit temporal functional diversification, while regulatory lymphocytes influence resolution by directing macrophage and stromal cell behavior (8). When immune responses fail to progress, inflammation does not resolve; fibrosis expands, microvascular integrity deteriorates, and the heart shifts toward chronic failure. Considering inflammation as a programmable, dynamic process establishes leukocytes as decisive regulators of cardiac fate.

Mechanistic Axis: Timing, Localization, and Immunometabolism Regulation

Leukocyte plasticity defines the dynamic immune response to cardiac injury. Monocytes, macrophages, neutrophils, and lymphocytes contribute to an orchestrated sequence that unfolds post-injury. Resident macrophages and recruited monocytes interact with dying cardiomyocytes, fibroblasts, and endothelial cells to coordinate debris clearance, angiogenesis, and extracellular matrix (ECM) turnover (9, 10). The early infiltration of neutrophils is followed by a transition to reparative macrophage populations that secrete pro-resolving mediators and growth factors (11). Disruption of this temporal sequence, either via persistent activation or premature resolution, can shift the outcome toward fibrosis and ventricular dysfunction (Figure 1) (12).

Figure 1: Leukocyte plasticity and cardiac repair.

Resident macrophages and recruited monocytes interact with dying cardiomyocytes, fibroblasts, and endothelial cells to coordinate debris clearance, angiogenesis, and extracellular matrix (ECM) turnover. Created in BioRender. Bagchi, R. (2026) https://BioRender.com/xoa7uyu.

Macrophage ontogeny further influences these processes. Cardiac macrophages arise from both embryonic progenitors and circulating monocytes, and these populations exhibit distinct functions (13). Embryonically derived resident macrophages support tissue homeostasis, angiogenesis, and electrical conduction, whereas recruited monocyte-derived macrophages dominate after injury and exhibit greater inflammatory plasticity (14). Disease progression is often associated with depletion or replacement of resident macrophages by recruited populations, potentially altering the balance between regenerative and inflammatory signaling.

Spatial context further dictates leukocyte function. Within the infarct border zone, macrophages assume a distinct transcriptomic identity compared with those in remote myocardium (15). Such localization-dependent phenotypes suggest that microenvironmental cues, including oxygen tension, matrix stiffness, and paracrine signaling, define tissue-level immune cell roles. These findings support that inflammation is not uniformly distributed but compartmentalized, reflecting a mosaic of pro-inflammatory and reparative niches within the same organ (16).

Metabolic reprogramming has also emerged as a key determinant of immune cell fate. Glycolytic activation supports rapid pro-inflammatory responses, while oxidative metabolism facilitates resolution and repair (17). Cardiac macrophages demonstrate remarkable metabolic flexibility, adapting to local substrate availability and signaling gradients. Targeting these metabolic checkpoints offers an avenue for modulating immune tone without broadly suppressing immune function. Such precision modulation could transform the therapeutic approach to post-infarction remodeling, chronic heart failure, and transplant adaptation (18).

These immune processes directly influence cardiac physiology. Leukocyte-regulated extracellular matrix deposition alters ventricular stiffness and compliance, while inflammatory signaling affects calcium handling and electrophysiological stability (19, 20). Resident macrophages also interact directly with cardiomyocytes to influence electrical conduction (21). Thus, leukocyte plasticity governs not only tissue structure but also functional cardiac performance.

Finally, leukocytes influence cardiac structure and function through crosstalk with stromal and parenchymal cells. Fibroblast activation and ECM deposition are strongly influenced by macrophage- and neutrophil-derived cytokines, including TGF-β, IL-10, and PDGF (22). Endothelial-leukocyte interactions guide angiogenesis and determine microvascular recovery (Figure 1). These intercellular exchanges form the biological substrate upon which repair, remodeling, or fibrosis unfolds (23).

Clinical Axis: Cardiovascular Disease, Aging, and Transplantation

Clinical and experimental cardiovascular biology present a persistent paradox. Inflammation is undeniably linked to disease risk and progression, yet efforts to broadly suppress immune activity have yielded inconsistent and often harmful results. Immune activation is neither incidental nor uniformly deleterious. Instead, it is prolonged, spatially patterned, and metabolically constrained in ways that challenge a simple inflammatory burden model.

Distinct leukocyte populations contribute differently across disease contexts. In atherosclerosis, endothelial activation recruits monocytes that differentiate into macrophages, driving plaque formation and destabilization (24). Neutrophils further contribute through inflammatory signaling and thrombotic interactions. In myocardial infarction, inflammatory leukocytes are essential for debris clearance and early repair, but failure to transition toward reparative macrophage states promotes fibrosis and ventricular remodeling (23, 25). In myocarditis, T-cell–mediated immune activation drives cardiomyocyte injury and persistent inflammation, illustrating lineage-specific immune contributions (26). These examples highlight that cardiovascular disease reflects dysregulation of specific immune trajectories rather than uniform inflammatory burden.

Targeted inflammatory interventions, including IL-1β inhibition in CANTOS or low-dose colchicine (COLCOT/LoDoCo2), reduced recurrent ischemic events independent of cholesterol lowering (27-29). However, these benefits are partial and accompanied by increased infection risk, indicating that immune suppression carries physiological cost. Anti-TNF therapies in heart failure (RENAISSANCE/RECOVER, ATTACH) failed to improve outcomes and increased harm at higher doses (30), while complement inhibition with pexelizumab (COMMA) and phospholipase inhibitors similarly failed despite strong preclinical rationale (30, 31). Even successful interventions reduced events without restoring regenerative repair (32). These findings suggest that immune activity must be guided rather than extinguished.

Aging further highlights the importance of immune plasticity. The aged myocardium exhibits chronic low-grade immune activation, impaired efferocytosis, and persistent inflammatory metabolism (23, 24). These changes coincide with reduced regenerative capacity and increased fibrosis. In contrast, neonatal mammalian hearts exhibit transient regenerative potential associated, with distinct immune environments enriched in reparative macrophage populations (32). This developmental transition suggests that immune programming, rather than cardiomyocyte limitations alone, constrains regenerative capacity in adult hearts.

Comparative models reinforce this conclusion. Zebrafish hearts regenerate efficiently following injury through macrophage-dependent processes involving debris clearance, angiogenesis, and inflammation resolution. Macrophage depletion impairs regeneration and promotes fibrosis, demonstrating that immune cells are required for repair (33). Mammalian hearts exhibit similar immune recruitment but often fail to complete reparative transitions, suggesting that regenerative failure may reflect incomplete immune state progression rather than the absence of immune activation (34, 35).

Transplantation further illustrates the dual nature of inflammation. Immune surveillance supports graft vascularization, remodeling, and integration, yet excessive activation promotes rejection and vasculopathy (36, 37). Conventional immunosuppression reduces the rejection risk but may impair regenerative immune functions. Selective modulation of leukocyte trafficking or regulatory immune populations may allow immune tolerance while preserving repair.

These observations suggest that leukocyte plasticity may serve both as a driver and a convergence point of disease. Systemic conditions such as aging, metabolic dysfunction, or ischemia alter tissue environments, constraining immune transitions and reinforcing maladaptive inflammation. Conversely, intrinsic defects in immune state progression may directly impair repair.

Integrative Outlook: Rethinking Inflammation as a Therapeutic Target for Regeneration

The next frontier in cardiovascular physiology lies in decoding and directing inflammation. Traditional paradigms have viewed leukocyte activation as an adverse event to be mitigated. Yet, mounting evidence now defines inflammation as a programmable system; an adaptable network governed by temporal, spatial, and metabolic parameters that can be therapeutically steered toward regeneration (45, 46). Recognizing this continuum positions immune modulation as a problem of control and timing, rather than merely blunt suppression.

Future therapies will likely depend on three interwoven dimensions of immune control. First, the temporal axis- inflammation should be targeted by phase, not by magnitude. Early intervention may preserve defensive competence, whereas late-phase modulation can accelerate resolution and tissue restitution (47). Second, the spatial axis- immune activity must be contextualized within the cardiac microenvironment. Targeting border-zone leukocytes may enhance angiogenesis and ECM remodeling while sparing remote myocardium from collateral injury (48). Third, the metabolic axis- transient reprogramming of leukocyte metabolism, through manipulation of metabolic pathways or mitochondrial dynamics, offers a means to bias immune tone toward repair without systemic immunosuppression (49).

Integration of these principles could institute a new research domain: immunoregenerative cardiology, thus defining the molecular rationale by which immune cells guide cardiac repair and establishing the basis for therapeutics that train rather than tame inflammation. For example, biomaterial scaffolds can deliver pro-resolving mediators or metabolic substrates in a spatiotemporally controlled manner (50). Gene- or cell-based therapies may recondition leukocyte subsets to adopt pro-repair transcriptional states that persist only during the healing window (51). In transplantation, selective targeting of leukocyte trafficking or checkpoint regulators may reconcile immune tolerance with regenerative integration (52). Macrophage metabolism suggests that immune tone could be shaped by altering substrate availability, biomechanical cues, or mitochondrial signaling (17).

These concepts collectively signal a shift from reactive to instructional immunotherapy, an approach that designs inflammatory trajectories rather than merely constraining them. By uniting mechanistic insight with translational innovation, this shift positions inflammation as a dynamic process that can be therapeutically programmed toward restoration rather than destruction.

Conclusion

The central insight emerging from modern cardiovascular immunobiology is unmistakable: inflammation is not the nemesis, but a blueprint. Leukocytes encode the instructions that determine whether the heart spirals into dysfunction or rebuilds itself. Every immunological signal, from the first wave of neutrophils to the metabolic reorientation of macrophages, represents a decision point in the trajectory of healing.

The mission before the field is no longer to silence these signals, but to understand them well enough to direct them. This requires abandoning the reflex to categorize inflammation as “excessive” or “detrimental.” Instead, we must recognize it as a programmable system whose regenerative capacity is embedded in leukocyte plasticity and shaped by local cues such as hypoxia, matrix composition, vascular access, and metabolic substrate availability (Figure 1). Rather than blunt immune activity systemically, interventions should be designed to guide immune responses through appropriate inflammatory and reparative states within defined tissue niches.

If cardiovascular biology embraces this shift, the implications are transformative. Precision immunotherapies could selectively reprogram leukocyte behavior at injury sites while preserving essential immune functions elsewhere. Regenerative programs could be activated rather than suppressed, and maladaptive immune persistence could be resolved without global immunosuppression. Heart failure, adverse remodeling, and even transplant rejection could be deemed as disorders of locally misdirected inflammation rather than irreversible, system-wide immune dysfunction.

The future of the field will belong to those willing to treat inflammation not as a liability but as a latent design for repair. Once we learn to read and rewrite this design, we will no longer be managing only the aftermath of injury; we will be engineering recovery.