Cholinergic blockade of neuroinflammation: from tissue to RNA regulators

Abstract

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.

Keywords: acetylcholine; aging; cholinergic; microRNA; neuroinflammation; sex.

Figure 1. The cholinergic anti-inflammatory pathway

(A) The proximity of cholinergic brain neurons to glia and the presence of AChRs on immune cells facilitate the cholinergic neuroimmune regulation. In peripheral tissues, communication of the ACh eliciting vagus nerve with the norepinephrine (NE) producing splenic nerve activates ACh production in T cells, where ACh initiates the cholinergic anti-inflammatory pathway by α7 nAChR activation and the suppression of pro-inflammatory cytokines secretion from splenic macrophages. (B) Molecular mechanisms involved in cholinergic anti-inflammatory actions involve the α7 nAChR-induced anti-inflammatory response that (1) inhibits the NF-κB pathway [43], (2) activates the JAK-STAT3 pathway (2) [41,45] or (3) up-regulates IRAK-M that attenuates TLR signaling (3) [46]. In addition, inflammatory stimuli up-regulate CHRNA7 and down-regulate its duplicated fused gene CHRFAM7A (4), thus promoting the anti-inflammatory actions [49].

Figure 2. Cholinergic-neuroimmune modulation of attention deficits and impaired cognitive functioning reflect brain transcript changes

(A) Higher cognitive functions such as attention are impaired in delirium and involve the prefrontal cortex (1), innervated by cholinergic neuron projections from cholinergic brain nuclei of the basal forebrain (2) and extending to the cholinergic anti-inflammatory brain–spleen circuit of the vagus nerve (3). (B) Age-dependent decline of CHRM3, ACHE, CHRNA7, CHRFAM7A, and SLC5A7 transcripts in the frontal cortex, basal ganglia and spleen. GTEx datasets of male and female transcript levels (blue and pink dots) change with age in both sexes. Note significant decreases in the frontal cortex for CHRM3 (r = −0.23, P=0.0081), CHRNA7 (r = −0.28, P=0.003), and SLC5A7 (r = −0.24; P=0.008), and in basal ganglia for CHRM3 (r = −0.22; P=0.0078), ACHE (r = −0.18; P=0.030) and CHRNA7 (r = −0.24; P=0.004). No significant change was observed in the spleen. Correlation is calculated using Spearman’s correlation test and green lines reflect linear fit. Adjusted P-values are FDR corrected. Subject numbers per the age groups of 20, 30, 40, 50, 60, 70 years were 5, 2, 13, 52, 85, 7 for frontal cortex; 7, 2, 21, 66, 94, 11 for basal ganglia; and 11, 19, 41, 60, 32, 3 for spleen.

Figure 3. Role of sncRNAs (miRs, tRFs) in the regulation of cholinergic anti-inflammatory pathway

Age-related decline of cholinergic transcripts in the prefrontal cortex might contribute to the susceptibility to age-related and/or disease-originated cognitive function deficits, whereas regulation at the level of sncRNAs might be a plausible future therapeutic intervention.