Curr Opin Immunol. 2025 Sep 17;97:102660. doi: 10.1016/j.coi.2025.102660. Online ahead of print.
ABSTRACT
The dogma of an impenetrable blood-brain barrier (BBB) has given way to the view that resident immune cells within the central nervous system respond to a variety of blood-borne soluble factors, particularly cytokines, and play an important functional role. In particular, microglia cells contribute to the regulation of neuroinflammation, with both protective and pathological roles. Specific microglia activation states variably influence the progression of neuroinflammatory and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. Significant evidence indicates that gut microbiota-derived products regulate microglial function across the lifespan and influence the BBB. Myeloperoxidase (MPO) catalyzes the conversion of hydrogen peroxide and chloride ions into hypochlorous acid, a potent oxidant implicated in oxidative tissue damage and modulation of inflammatory signaling. Elevated MPO levels in the central nervous system have been correlated with human disease and the dysregulation of MPO activity in microglia is particularly detrimental, as it amplifies the oxidative stress, disrupts the BBB integrity, and potentiates the neuroinflammatory cascades through the activation of transcription factors like NF-κB. Targeting MPO activity through selective inhibitors or antioxidant strategies may attenuate microglial activation and reduce neuroinflammation, highlighting its potential as a therapeutic target, but the regulatory mechanisms governing MPO expression in microglia and its interplay with other inflammatory mediators remain poorly understood. New research efforts into the relationship between gut microbiota, microglia, MPO, and neuroinflammation are essential to unravel the complexities of neuropathology in a variety of conditions beyond neurodegenerative diseases.
PMID:40972344 | DOI:10.1016/j.coi.2025.102660