Immunometabolic insights into the foreign body response

Abstract

Differences in energy use by immune cells cause long-lasting inflammation, with higher glucose uptake strongly linked to the formation of scar tissue around implanted materials.

When implanted into a host, biomaterials elicit varying levels of inflammation and fibrosis. However, the foreign body response (FBR) is characterized by chronic inflammation and excessive fibrosis, both of which impair critical functional outcomes such as effective tissue-implant integration. More concerning, the FBR can induce neoplasia, leading to cellular transformation and, potentially, the onset of cancer. Given these risks, it is critical to fully understand the molecular basis of the FBR.

Recent advances at the intersection of translational immunology and metabolism are revolutionizing our understanding of the FBR to commonly used biomaterials, challenging longstanding assumptions. For example, polylactide (PLA) was once thought to cause immune activation via low pH resulting from lactic acid breakdown products. However, new findings have called this view into question, demonstrating that PLA degradation produces lactate-based by-products that mediate profound shifts in immune cell metabolism and bioenergetics within the implant microenvironment—effects that occur independently of pH (1). Notably, the stereochemistry of PLA further affects these immune responses (2), with certain chiral configurations driving an increased dependence on glycolysis, a metabolic pathway fundamental to immune cell activation. Accordingly, small molecules targeting glycolytic flux can, in fact, more effectively modulate both inflammatory and fibrotic outcomes compared to the neutralizing salts currently used in clinics (3). Metabolic reprogramming in the biomaterial microenvironment influences the movement of neutrophils and monocytes through expressed cell surface proteins, including C-C motif chemokine receptor 2 (CCR2) and C-X3-C motif chemokine receptor 1 (CX3CR1), and shapes the composition and polarization states of macrophages and dendritic cells (3). Similar metabolic reprogramming has also been observed with other biomaterial implants, including hydroxyapatite (4), cellulose (5), and polyethylene (6), each associated with increased glucose uptake in the FBR.

Nevertheless, the spatiotemporal transcriptional landscape underlying glycolytic reprogramming and the precise impact of metabolic heterogeneity in the FBR remain unclear. Comprehensive mapping of these spatial and temporal immunometabolic changes within the implant microenvironment promises to establish a new standard for evaluating biocompatibility, ultimately enabling nuanced control of inflammatory outcomes and ensuring successful clinical deployment of implanted biomaterials in regenerative engineering.

In this issue of Science Advances, Rempe et al. (7) unravel the spatiotemporal changes in glycolysis that underlie the FBR, revealing a sustained reliance on glucose uptake as a hallmark of pro-inflammatory macrophages and multinucleated giant cells (Fig. 1, top) across a range of clinically used polymers, such as polypropylene applied in the surgical repair of hernia, polyethylene used in total knee and hip replacement surgeries, and silicone (polydimethylsiloxane) used in breast implants. The temporal study design enabled a nuanced dissection of pro- and anti-inflammatory cytokine dynamics, demonstrating, for example, that macrophage major histocompatibility complex class II expression is present in oxidative cells during the acute phase and in glycolytic cells during the chronic phase of the FBR, respectively. These advances were enabled by the authors’ use of multimodal approaches, notably multiparametric flow cytometry integrated with metabolic profiling (via cell identification and puromycinylation) and imaging at single-cell resolution.

Fig. 1. Heterogeneity in the FBR.

(Top) Shifts in metabolic profiles drive complex interactions among diverse cell populations, fueling prolonged inflammation and excessive fibrosis in FBR. (Bottom) Macrophages show high and low GLUT1 expression at different stages after implantation of clinically relevant polymers. Notably, GLUT1^Hi macrophages display oxidative stress and ramped-up fatty acid synthesis, likely for pro-inflammatory lipid (e.g., prostaglandin) production, and colocalize with myofibroblasts to promote fibrotic capsule development. The anaerobic, fibrotic microenvironment amplifies hypoxia, increasing further reliance on glycolysis. Multinucleated giant cells, products of macrophage fusion via frustrated phagocytosis, also rely highly on glycolysis. These findings lay the groundwork for investigating how metabolic heterogeneity drives cross-talk among parenchymal, immune, and stromal cells within the implant niche. Fully decoding these immunometabolic vulnerabilities is key to engineering next-generation biomaterials with proregenerative functional outcomes.

In particular, the findings by Rempe et al. (7) on silicone implants uncover an added layer of complexity in the metabolic programs at the implant-tissue interface, introducing the concept of metabolic heterogeneity as a defining feature of the FBR. By stratifying macrophages based on high or low expression of the glucose transporter GLUT1, the authors identify metabolically distinct subsets. Specifically, macrophages with elevated GLUT1 (GLUT1^Hi) exhibit enhanced fatty acid synthesis, rather than oxidation—a phenotype instrumental in the production of proinflammatory lipids such as prostaglandins and leukotrienes (8)—thereby unveiling previously unappreciated mechanisms driving pro-inflammatory disease progression in the FBR context (Fig. 1, bottom).

These GLUT1^Hi macrophages colocalize with activated fibroblasts within the fibrotic capsule surrounding implanted biomaterials, establishing a spatial association among metabolic rewiring, inflammation, and fibrotic tissue remodeling (Fig. 1, bottom). Moreover, macrophages with elevated GLUT1 expression show increased levels of proteins associated with oxidative stress [e.g., PRDX2 and glucose-6-phosphate dehydrogenase (G6PD)]—a finding further validated by single-cell transcriptomic analysis of public datasets (Fig. 1, bottom). These GLUT1^Hi macrophages exhibit metabolic bottlenecks at both entry and exit points in the glycolytic pathway—reduced hexokinase 1 (HK1) and pyruvate kinase M (PKM) expression—thereby pathologically regulating glycolytic flux. Despite maintaining similar succinate dehydrogenase complex subunit A (SDHA) levels, these GLUT1^Hi macrophages have increased mitochondrial mass relative to their counterparts expressing low levels of GLUT1 (GLUT1^Lo), further underscoring the complex and nuanced metabolic heterogeneity that underlies the FBR.

Together, these exciting findings lay the groundwork for establishing immune cell metabolism as a defining criterion in the assessment of biomaterial biocompatibility and open new horizons for strategic interventions that modulate the local biomaterial microenvironment to enhance regenerative engineering (9, 10). Accordingly, the incorporation of small molecule glycolytic inhibitors in polymeric biomaterials has been shown to recompose the implant microenvironment, altering the composition and activation states of neutrophils, monocytes, macrophages, dendritic cells, and T cells toward a proregenerative phenotype (3), although these results require validation in large animal models. While the proximity of highly glycolytic macrophages to fibroblasts has been established (7), further studies investigating macrophage-myofibroblast metabolic cell communication will reveal key insights into the cellular cross-talk and signaling pathways that sustain the FBR, with implications for fibrotic diseases affecting different organ systems. This mechanistic understanding could inform design strategies for next-generation biomaterials to not only mitigate chronic inflammation and excessive fibrosis but also actively promote functional tissue integration and long-term implant success.

This research draws a notable parallel to the tumor microenvironment (TME), the FBR as proinflammatory and the TME as largely immunosuppressive—highlighting fundamental similarities in the metabolic programming of both disease contexts. The insights gleaned from comparing these two systems not only expand our mechanistic understanding of the FBR but also foster a rich dialog between fields, suggesting that strategies effective in one setting may inform transformative therapies in the other.