Inflammatory stimuli and consequent pro-inflammatory immune responses may facilitate neurodegeneration and threaten survival following pathogen
infection or
trauma, but potential controllers preventing these risks are incompletely understood. Here, we argue that small
RNA regulators of
acetylcholine (ACh) signaling, including
microRNAs (miRs) and
transfer RNA fragments (tRFs) may tilt the balance between innate and adaptive immunity, avoid chronic
inflammation and prevent the
neuroinflammation-mediated exacerbation of many neurological diseases. While the restrictive permeability of the blood-brain barrier (BBB) protects the brain from peripheral immune events, this barrier can be disrupted by
inflammation and is weakened with age. The consequently dysregulated balance between pro- and anti-inflammatory processes may modify the immune activities of brain microglia, astrocytes, perivascular macrophages, oligodendrocytes and dendritic cells, leading to neuronal damage. Notably, the vagus nerve mediates the peripheral
cholinergic anti-inflammatory reflex and underlines the consistent control of body-
brain inflammation by pro-inflammatory
cytokines, which affect
cholinergic functions; therefore, the disruption of this reflex can exacerbate
cognitive impairments such as attention deficits and
delirium.
RNA regulators can contribute to re-balancing the
cholinergic network and avoiding its chronic deterioration, and their activities may differ between men and women and/or wear off with age. This can lead to
hypersensitivity of aged patients to
inflammation and higher risks of
neuroinflammation-driven
cholinergic impairments such as
delirium and
dementia following
COVID-19 infection. The age- and sex-driven differences in post-transcriptional
RNA regulators of
cholinergic elements may hence indicate new personalized therapeutic options for
neuroinflammatory diseases.