Air Pollution May Push the Immune System from Adaptation into Dysfunction

Air pollution is increasingly recognized as an environmental factor associated with immune dysfunction and heightened disease susceptibility, and a new narrative review published in Discover Life on 27 October 2026 brings together the molecular and cellular evidence behind that link. The review, led by Avetis Tsaturyan and colleagues, synthesizes findings on particulate matter, ozone, nitrogen dioxide, polycyclic aromatic hydrocarbons, metals, wildfire smoke, pollen and microbial aerosols, and proposes a multidimensional framework for understanding when the immune system’s protective responses tip over into maladaptive dysregulation. The authors searched PubMed, Web of Science and Scopus for literature published primarily between January 2000 and July 2026, with the final search conducted on 15 July 2026, and their synthesis draws on 110 cited sources.

The central message is that pollutant exposure can induce oxidative stress, mitochondrial dysfunction, epithelial barrier injury, inflammatory signaling, epigenetic alterations and dysregulation of both innate and adaptive immune-cell functions. These responses are highly context-dependent, varying with pollutant composition, concentration, exposure duration, co-exposures, the experimental model used and the susceptibility of the host. The review deliberately distinguishes evidence from human epidemiological studies, controlled human-exposure experiments, animal models and in vitro systems, because these designs differ substantially in what they can establish about causality, mechanism and clinical relevance.

The respiratory tract is the primary interface between inhaled pollutants and the immune system, and the review identifies epithelial barrier dysfunction as an important initiating and amplifying event. Experimental studies indicate that PM2.5, ozone, nitrogen dioxide and diesel exhaust particles can impair epithelial integrity, in part by altering tight-junction proteins such as occludin, claudins and zonula occludens-1, thereby increasing permeability. Barrier disruption has been demonstrated in in vitro epithelial systems and animal models, although some experimental studies use exposure concentrations above typical ambient levels, which limits direct extrapolation to environmental human exposure. Pollutant-exposed epithelial cells can also release alarmins including IL-33, IL-25 and thymic stromal lymphopoietin, which activate dendritic cells and type 2 innate lymphoid cells and may contribute to allergic inflammation, particularly when allergen co-exposure or pre-existing airway disease is present.

Oxidative stress emerges as one of the most consistently reported biological responses. Particulate matter can generate reactive oxygen species through redox-active surface components, transition metals and adsorbed organic compounds, while ozone reacts primarily with constituents of respiratory lining fluid and cell membranes to generate secondary oxidation products. Excessive reactive oxygen formation can promote lipid peroxidation, protein oxidation, mitochondrial dysfunction and DNA damage. In human bronchial epithelial-cell models, PM2.5 exposure has been reported to induce pyroptosis through reactive-oxygen-species-associated NF-kappaB and inflammasome-related signaling. Most direct mechanistic evidence for these processes, however, derives from cellular and animal models, and their quantitative relevance under environmentally realistic human exposure remains less precisely defined.

Inflammatory signaling pathways show marked context dependency. In vitro and animal studies suggest that particulate matter can activate NF-kappaB and MAPK signaling, increasing cytokines and chemokines such as IL-1beta, IL-6, IL-8 and TNF-alpha. NLRP3 inflammasome activation has been observed in experimental models exposed to particulate matter, yet other studies report that PM2.5 exposure may impair inflammasome and interferon responses during viral infection. The review concludes that NLRP3 should be considered a context-dependent pathway rather than a universal marker of pollutant toxicity, with effects depending on exposure timing, concentration, cell type and infection status. Recent single-cell transcriptomic work in ozone-exposed mice further showed that alveolar-macrophage responses are heterogeneous and cell-state-specific, and that prior acute ozone injury modifies responses to subsequent repetitive exposure.

Among adaptive immune cells, the evidence is similarly nuanced. Controlled human challenge studies provide evidence that combined diesel-exhaust-particle and allergen exposure can enhance allergen-specific IgE production and promote a Th2-associated cytokine pattern, while experimental work with urban particulate matter shows that pollutant-activated human dendritic cells can promote mixed inflammatory Th1, Th2 and Th17 responses. Human studies in children with asthma have associated elevated ambient air-pollution exposure with reduced regulatory T-cell suppressive function and altered methylation of FOXP3-associated regulatory regions, although methylation changes alone do not establish causality. In the COVICAT cohort, higher long-term pollutant exposure was associated with reduced antibody responses following COVID-19 vaccination, and a study of vaccinated older adults in Northern Italy reported associations between long-term air pollution, breakthrough SARS-CoV-2 infection and antibody responses. These observations are population- and vaccine-specific and should not be generalized to humoral immunity as a whole.

At the clinical level, epidemiological evidence most consistently associates air pollution with exacerbation of asthma and allergic respiratory disease, chronic respiratory disease, and cardiovascular or systemic inflammatory outcomes, while evidence for respiratory infections and pregnancy-related immune effects is more heterogeneous. Long-term exposure to mixtures of sulfur dioxide, nitrogen dioxide and PM2.5 has been associated with anti-citrullinated protein antibody positivity, a finding relevant to rheumatoid autoimmunity that does not demonstrate that pollution directly causes rheumatoid arthritis. Associations have also been reported for rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis, though results vary across populations. Susceptibility is not evenly distributed: children, older adults, pregnant individuals, people with pre-existing disease and socioeconomically disadvantaged populations may face heightened vulnerability through both biological factors and unequal exposure, and population-based evidence indicates stronger pollution-associated mortality in some deprived populations.

The review’s most distinctive contribution is its operational framework for adaptive resilience, defined as the capacity of a biological system to maintain, regain or reorganize functional homeostasis during and after air-pollution exposure without progressing to persistent immune dysfunction or irreversible tissue injury. Within this framework, adaptation refers to inducible responses that reduce immediate perturbation, compensation describes the additional biological effort needed to maintain function under continuing stress, tolerance denotes reduced inflammatory responsiveness during repeated exposure, recovery is the return of function toward the pre-exposure state, and maladaptation is persistent failure of protective and repair mechanisms accompanied by incomplete recovery and loss of functional reserve. The same pathway can be protective when transient, compensatory when persistently required, or maladaptive when activation no longer prevents progressive dysfunction. Candidate resilience mechanisms include Nrf2-dependent antioxidant signaling, autophagy and mitochondrial quality control, epithelial repair, immune regulation and microbiome-associated responses, but the authors caution that activation of these pathways should not itself be equated with resilience.

Importantly, the review emphasizes that reduced inflammatory responsiveness should not automatically be read as beneficial tolerance. Diminished cytokine production may instead reflect metabolic dysfunction, cellular exhaustion or impaired antigen presentation, and evidence of preserved antimicrobial and tissue function is required before reduced responsiveness can be classified as protective. The authors also note that no universal quantitative exposure threshold currently defines where adaptive resilience becomes maladaptive dysregulation; such a transition is likely to be pollutant-, tissue-, host- and time-dependent, and is better understood functionally, through failure to restore homeostasis between exposure episodes, than through any fixed pollutant concentration. Recovery after air-pollution exposure remains insufficiently characterized by longitudinal human studies, since many epidemiological investigations assess exposure and outcomes only at discrete time points.

As a narrative review, the work involved no formal PRISMA-based screening process, prospective protocol, quantitative risk-of-bias assessment, meta-analysis or systematic evidence grading, and the authors acknowledge the possibility of selection bias and incomplete retrieval of relevant studies. Its conclusions should therefore be read as a critical synthesis of converging and conflicting evidence rather than as quantitative effect estimates. The authors identify priorities for future research, including multipollutant and sequential exposure models, longitudinal cohorts with repeated exposure assessment and immune profiling, harmonized pollutant characterization, human-relevant experimental platforms such as air-liquid-interface cultures and organ-on-chip systems, and multi-omics integration within exposome-oriented frameworks. Until mechanistic and precision-prevention strategies are better validated, they conclude that reducing harmful environmental exposure remains a well-supported public-health approach for limiting pollution-associated immune and clinical effects.

Subject of Research: How air pollution affects immune regulation and adaptive resilience

Article Title: Immune dysregulation and adaptive resilience in response to air pollution

Article References: Tsaturyan, A., Stepanyan, L., Goginyan, V., Azizyan, H., Balayan, L., Saribekyan, Z., Sargsyan, T., & Roviello, G. (2026). Immune dysregulation and adaptive resilience in response to air pollution. Discover Life, 56(1), Article 51. https://doi.org/10.1007/s11084-026-09772-2

Image Credits: AI Generated

DOI: 10.1007/s11084-026-09772-2

Keywords: air pollution, immune dysregulation, particulate matter, oxidative stress, epithelial barrier, regulatory T cells, NLRP3 inflammasome, gut-lung axis, wildfire smoke, adaptive resilience, exposome, vaccine responses