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, 38 (3), 282-294

Neuroimmune Interactions and Kidney Disease


Neuroimmune Interactions and Kidney Disease

Sho Hasegawa et al. Kidney Res Clin Pract.


The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a well-studied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic anti-inflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.

Keywords: Autonomic nervous system; Cholinergic neurons; Imaging; Optogenetics; Sympathetic nervous system; Vagus nerve stimulation; three-dimensional.

Conflict of interest statement

Conflicts of interest

Reiko Inagi has received research funding from Kyowa-Hakko-Kirin. Sho Hasegawa and Tsuyoshi Inoue have no competing interests.


Figure 1
Figure 1. The cholinergic anti-inflammatory pathway.
The cholinergic anti-inflammatory pathway bridges the nervous and immune systems. Afferent vagus nerves are stimulated by proinflammatory cytokines. The signal activates efferent vagus nerves via the nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) in the brain. Activated efferent vagus nerves stimulate splenic nerves, resulting in release of norepinephrine (NE). CD4-positive T cells in the spleen release acetylcholine (ACh) after NE binds to β2 adrenergic receptors (β2AR). Alpha 7 subunit of the nicotinic acetylcholine receptor (α7nAChR)-positive macrophages receive Ach, leading to anti-inflammatory responses such as release of tumor necrosis factor alpha (TNF-α). The dotted lines are strongly suggested, though not conclusively proven, pathways. SGN, sympathetic ganglionic neuron; SPGN, sympathetic preganglionic neuron.
Figure 2
Figure 2. Mechanisms of cholinergic anti-inflammatory pathway activation between vagus nerve stimulation and C1 neuron stimulation.
Subdiaphragmatic vagotomy does not abolish renal protection, indicating that C1 neuron-mediated cholinergic anti-inflammatory pathway (CAP) activation does not occur via a parasympathetic route but via a sympathetic route. The mechanism of CAP activation via C1 neurons (sympathetic) might differ from that via vagus nerve stimulation (parasympathetic). The dotted lines are strongly suggested, though not conclusively proven, pathways. Ach, acetylcholine; α7nAChR, alpha 7 subunit of the nicotinic acetylcholine receptor; β2AR, β2 adrenergic receptor; DMV, dorsal motor nucleus of the vagus; NE, norepinephrine; SGN, sympathetic ganglionic neuron; SPGN, sympathetic preganglionic neuron; TNF-α, tumor necrosis factor alpha.
Figure 3
Figure 3. Three-dimensional distribution of sympathetic nerves and arteries in the kidney.
The kidney was optically cleared and subjected to immunofluorescent staining with antibodies against tyrosine hydroxylase (TH) and anti-alpha smooth muscle actin (αSMA). Sympathetic nerves (TH, green) are primarily distributed in parallel with arteries (αSMA, magenta).
Figure 4
Figure 4. Time-course of sympathetic denervation after ischemia-reperfusion injury (IRI).
Three-dimensional imaging reveals that sympathetic innervation density declines in injured kidneys. This sympathetic denervation was persistent even 28 days after injury, although innervation drastically decreased at day 4 and partially recovered over time.

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