Immunotoxicological mechanisms of microplastics: A Molecular Perspective

The proliferation of plastic waste has consolidated microplastics (MPs) and nanoplastics (NPs) as ubiquitous pollutants in the biosphere. Humanity has crossed an unprecedented geological and biological threshold: the transition to the "Plastic Anthropocene." What began as a materials revolution in the 1950s has transformed into a systemic infiltration of synthetic particles into every crner of the biosphere. For humans, this is not only an environmental concern but also a daily physiological reality.

Human exposure is a documented reality, with ingestion being the predominant route through drinking water, table salt, fish, and various foods. Unlike biological pathogens, the human body does not possess evolutionary pathways for the enzymatic degradation of persistent synthetic polymers such as polyethylene (PE) or polystyrene (PS) (Table. 1).

Table 1: Estimates of indoor suspended MP fragment concentrations, based on all available literature observations in the 1.0 - 300 µm range. Table reproduced from: Yakovenko et al. (2025) PLOS One

This chronic exposure raises a central question for modern immunotoxicology: What actually happens inside our cells when this non-biodegradable material attempts to be processed by an immune system that lacks an evolutionary degradation pathway for synthetic polymers? Studying the immunotoxicological mechanisms of microplastics is fundamental to understanding how these polymer particles interact with our immune cells and trigger inflammatory responses, since they cannot be hydrolyzed or digested by natural enzymes, micro- and nanoplastics (MNPs) force our defenses into a state of constant alert.

The gastrointestinal tract constitutes the primary interface of exposure. This defensive barrier includes intestinal alkaline phosphatase (IAP) and the epithelium sealed by tight junctions. Scientific evidence demonstrates that particle translocation is critically dependent on particle size.

Nanoplastics (<100 nm) possess the ability to passively diffuse via the paracellular pathway, altering the expression of tight junction proteins and inducing intestinal permeability. Larger microplastics (<150 µm) can be internalized via transcytosis through M cells in Peyer's patches, reaching the lymphatic and systemic circulation.

Upon entering biological fluids (such as plasma), the polymer's original hydrophobic surface spontaneously adsorbs endogenous proteins and lipids, forming a dynamic structure known as a "protein crown" or biocrown. This process is governed by the Vroman effect, where low-molecular-weight proteins are progressively replaced by high-affinity proteins.

Recent proteomic research in journals such as Analytical Chemistry indicates that PVC and PE particles acquire a biocrown enriched in apolipoprotein A1 (ApoA1). This coating gives the particle an identity similar to high-density lipoproteins (HDL), allowing it to interact with cell receptors (such as SR-B1) and facilitating its endocytosis by macrophages. a mechanism that the literature often describes as a "Trojan Horse" effect. (Fig. 1).

FIg.. 1: Photocatalytic proximity labeling enables identification of proteins forming the nanoplastic protein corona. Figure reproduced from: Wang, J. Y., et al. (2024). Analytical Chemistry. ACS Publications.

Macrophages are remarkably efficient at internalizing polystyrene particles and other polymers up to 10 µm in size. After phagocytosis, the particle is enclosed in a phagosome, which subsequently fuses with lysosomes loaded with hydrolytic enzymes and an acidic pH. The fundamental problem is that plastics are resistant to these enzymes. This inability to degrade them leads to persistent intracellular accumulation that disrupts lysosomal function.

The chronic presence of MNPs in macrophages induces a metabolic and functional transition known as polarization. Data and scientific studies on this topic suggest that exposure to plastic predominantly promotes an M1 phenotype (classically activated), characterized by the production of reactive oxygen species (ROS), nitric oxide, and pro-inflammatory cytokines such as IL-6, TNF-alpha, and IL-1-beta. However, under certain conditions of chronic exposure or with specific polymers such as hydrophilic polyurethane, polarization towards M2 (alternatively activated) has been observed, linked to tissue repair and fibrosis.

Furthermore, when a macrophage or neutrophil attempts to engulf a particle that exceeds its physical capabilities (due to its large size, such as microplastics >20 µm), a phenomenon known as frustrated phagocytosis is triggered. Lysosomal instability causes the release of enzymes and reactive oxygen species (ROS) into the extracellular space, causing oxidative stress in the surrounding tissue. Intracellularly, this disruption activates the NLRP3 inflammasome, whose activation recruits caspase-1, an enzyme that processes proinflammatory cytokines (IL-1β and IL-6) and cleaves gasdermin D to form pores in the cell membrane. The result is pyroptosis, a violent programmed cell death that releases reactive oxygen species (ROS) and lysosomal enzymes into the extracellular space. (Fig. 2).

Fig. 2: Mechanism of inflammasome activation by particulates. Figure reproduced from: Zhu, S., et al. (2024). Particle and Fibre Toxicology.

This process does not affect the plastic itself, but it can induce massive damage to the surrounding healthy tissue, perpetuating a state of chronic inflammation and fibrosis. Simultaneously, plastic surfaces act as platforms that activate the alternative pathway of the complement system, releasing anaphylatoxins (C3a and C5a) into the plasma.

The interaction of plastic with cellular structures can force changes in host proteins, creating "neoantigens" that the immune system no longer recognizes as self. However, the deeper molecular mechanism is the activation of the cGAS-STING axis. Plastic-induced mitochondrial damage causes the leakage of mitochondrial DNA (mtDNA) into the cytosol, which the immune system interprets as a sign of viral invasion. This erroneous activation induces the activation of interferon-like pathways observed in experimental models and an increase in antinuclear antibodies (ANA). With the loss of self-tolerance, the risk of developing autoimmune mechanisms increases significantly, although evidence in humans is currently limited.

Furthermore, the inability of our immune system to degrade, combat, or eliminate MNPs can lead to long-term bioaccumulation. Emerging evidence suggests that micro and nanoplastics can translocate to human tissues and may persist transiently; however, robust evidence demonstrating long-term bioaccumulation in human organs is still lacking.

We are facing an emerging area of ​​scientific concern that demands a new vision of clinical immunology, where environmental surveillance and the study of persistent xenobiotics are fundamental pillars of diagnosis.

If the immune system reflects our interaction with the environment, what is the increasing exposure to microplastics revealing about their long-term effects?

Emilio J. Orovengua

Biochemist | Science Communicator | Microplastic Specialist