Environmental influences on macrophage epigenetics and trained immunity: a review

Macrophages are central to host immunity and tissue homeostasis, exhibiting remarkable functional plasticity across a continuum of states-ranging from pro-inflammatory (M1-like) to anti-inflammatory and tissue-reparative (M2-like) phenotypes. Environmental exposures can induce persistent epigenetic changes that shape macrophage responses well beyond the acute phase, a phenomenon now recognized as trained immunity. This narrative review synthesizes current knowledge on how diverse components of the exposome-including diet, air pollution, agricultural chemicals, heavy metals, endocrine-disrupting chemicals, per- and polyfluoroalkyl substances (PFAS), alcohol, smoking, the gut microbiome, maternal diet, and psychosocial stress-remodel the macrophage epigenome. We examine the underlying epigenetic mechanisms, namely DNA methylation, histone modifications, and non-coding RNAs, and discuss their impact on macrophage polarization, cytokine production, and trained immunity induction. Special emphasis is placed on the distinction between bona fide trained immunity and transient inflammatory skewing, the limitations of the classical M1/M2 framework, and the identification of "epigenetic vulnerability nodes" at which multiple environmental signals converge on a small set of chromatin-modifying enzymes and transcription factors. We also highlight critical knowledge gaps, including the lack of data for emerging contaminants such as micro- and nanoplastics, the uncertain reversibility of exposure-induced epigenetic marks, and the challenge of demonstrating transgenerational inheritance in humans. By connecting molecular mechanisms with broader public health implications, this review provides a critical framework for understanding environmentally driven immune dysregulation and outlines future research directions, including mixture toxicology, single-cell multi-omics, and the integration of epigenetic endpoints into chemical risk assessment.