NF-κB is important in inflammatory signaling, and one of many possible targets for suppression of inflammation. The usual caveats apply, in that unwanted, harmful, chronic inflammation uses the same signaling pathways as normal, necessary, short-term inflammatory responses to pathogens and injury. Researchers have yet to find a suppression approach that only affects chronic inflammation, and does not also suppress beneficial functions of the immune system. In principle the only reliable way to achieve that goal is to remove the damage of aging that causes inflammation, which is not presently the primary focus of researchers concerned with inflammation.
Neuroinflammation, a significant contributor to various neurodegenerative diseases, is strongly associated with the aging process; however, to date, no efficacious treatments for neuroinflammation have been developed. In aged mouse brains, the number of infiltrating immune cells increases, and the key transcription factor associated with increased chemokine levels is nuclear factor kappa B (NF-κB). Exosomes are potent therapeutics or drug delivery vehicles for various materials, including proteins and regulatory genes, to target cells.
In the present study, we evaluated the therapeutic efficacy of exosomes loaded with a nondegradable form of IκB (Exo-srIκB), which inhibits the nuclear translocation of NF-κB to suppress age-related neuroinflammation. Single-cell RNA sequencing revealed that these anti-inflammatory exosomes targeted macrophages and microglia, reducing the expression of inflammation-related genes. Treatment with Exo-srIκB also suppressed the interactions between macrophages/microglia and T cells and B cells in the aged brain. We demonstrated that Exo-srIκB successfully alleviates neuroinflammation by primarily targeting activated macrophages and partially modulating the functions of age-related interferon-responsive microglia in the brain.
Thus, our findings highlight Exo-srIκB as a potential therapeutic agent for treating age-related neuroinflammation.
Link: https://doi.org/10.1038/s12276-024-01388-8
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