Chronic exposure to environmental pollutants and molecular reprogramming of microglia in ischemic stroke

Over the past two decades, the incidence of stroke in individuals under the age of 70 has steadily increased. This rise is partly driven by modifiable environmental risk factors, among which air pollution has emerged as a major contributor. Exposure to particulate matter is now considered the second leading risk factor for stroke, surpassed only by high blood pressure. Both clinical and preclinical studies indicate that these particles can accumulate in the brain, promoting neuroinflammation and increasing the risk of neurological damage. At the center of the brain’s immune response are microglia, the resident immune cells that play a key role in determining tissue damage and recovery after stroke. Growing evidence suggests that environmental pollutants can activate microglia and contribute to neuronal injury. However, the molecular mechanisms underlying these effects remain poorly understood. Microglia are highly sensitive to changes in their surrounding environment, which can induce long-lasting epigenetic reprogramming and shape their response to subsequent challenges, such as stroke. In addition to environmental exposures, microglial function is strongly influenced by internal signals, including metabolites produced by the gut microbiota. Short-chain fatty acids (SCFAs), for example, have been shown to modulate microglial morphology, gene expression, and epigenetic states, and to exert neuroprotective effects in stroke by supporting synaptic plasticity and long-term functional recovery. Importantly, environmental pollutants can disrupt the gut microbiota, leading to the production of harmful metabolites that may further alter microglial activation and worsen stroke outcomes.

This project is based on the hypothesis that chronic exposure to environmental pollutants modifies microglial immune responses through multiple, interconnected pathways: i. direct effects of toxins on microglia; ii. activation of peripheral immune cells that subsequently interact with the brain; iii. and pollution-induced alterations of the gut microbiota and its metabolic output. Within the DFG Priority Programme SPP 2395, “Local and peripheral drivers of microglia diversity and function,” we aim to clarify how these mechanisms converge to influence stroke severity. To address this, we will characterize microglial epigenetic changes following acute and chronic pollutant exposure, assess their impact on stroke outcome, and investigate how environmental pollutants reshape gut microbiota composition and function. Building on our previous findings that T cells can traffic from the gut to the brain after stroke, we will investigate whether pollutant exposure promotes peripheral immune activation and T cell migration, thereby influencing microglial transcriptional and epigenetic profiles. Finally, we will test whether targeting epigenetic pathways or modulating the gut microbiota can mitigate the detrimental effects of environmental pollutants on microglia and improve stroke recovery.