AKI and the Neuroimmune Axis

Abstract

Neuroimmune interaction is an emerging concept, wherein the nervous system modulates the immune system and vice versa. This concept is gaining attention as a novel therapeutic target in various inflammatory diseases including acute kidney injury (AKI). Vagus nerve stimulation or treatment with pulsed ultrasound activates the cholinergic anti-inflammatory pathway to prevent AKI in mice. The kidneys are innervated by sympathetic efferent and sensory afferent neurons, and these neurons also may play a role in the modulation of inflammation in AKI. In this review, we discuss several neural circuits with respect to the control of renal inflammation and AKI as well as optogenetics as a novel tool for understanding these complex neural circuits.

Keywords: Acute kidney injury; cholinergic anti-inflammatory pathway; neuroimmune interaction; optogenetics; vagus nerve stimulation.

Figure 1.

The inflammatory reflex. When inflammation occurs in peripheral tissues, inflammatory cytokines, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs) bind to cytokine receptors and pattern recognition receptors (PRRs) expressed on the local afferent vagus nerve. The signal is transmitted through the CNS to the efferent vagus nerve and the splenic nerve. Norepinephrine released by splenic nerve terminals binds to β2-adrenergic receptors expressed on choline acetyltransferase (ChAT)-positive T cells, causing acetylcholine release from this specific T cell subpopulation. The released acetylcholine binds to α7nAChRs expressed on macrophages located close to these T cells, resulting in suppressed production of the proinflammatory cytokines by the macrophages and reduced inflammation. Abbreviations: DMV, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius.

Figure 2.

(A) Inhibitory and (B) excitatory renorenal reflexes. An increase in the ERSNA is known to increase the ARNA. (A) In normal kidneys, an increase in ARNA suppresses ERSNA, providing negative feedback to prevent excessive ERSNA (inhibitory renorenal reflex). (B) In contrast, in the kidneys, under pathologic conditions such as hypertension, CKD, and heart failure, the inhibitory renorenal reflex is suppressed and an excitatory reflex prevails. The afferent renal nerves from the damaged kidneys exert an excitatory influence on ERSNA, forming a vicious cycle leading to excessive ERSNA.

Figure 3.

The hypothesized interaction between the spleen and the kidney for the activation of dendritic cells (DCs) and T cells in angiotensin II (Ang II)-induced hypertension. Ang II with renal sympathetic nerve activity activates DCs in the kidney, leading to the migration of these cells to the spleen, where they, in turn, activate T cells. Thereafter, these activated T cells egress from the spleen and migrate to the kidney causing inflammation and hypertension. The splenic nerve is essential for T cell migration.

Figure 4.

Schematics of an (A) excitatory light-sensitive opsin, ChR2, and (B) inhibitory light-sensitive opsins, halorhodopsin, and archaerhodopsin. The expression of these opsins does not affect the resting membrane potential because of the lack of ion flux without light application. (A) When ChR2 is illuminated with blue light, the gate of this nonselective cation channel is opened, which allows influx of Na⁺ and causes depolarization of the ChR2-expressing neurons. If the spike of Na⁺ entry is large enough for the membrane potential to reach the threshold, an action potential is evoked. (B) When halorhodopsin/archaerhodopsin is illuminated with yellow/green light, it functions as an inward Cl^-/outward H⁺ pump and causes hyperpolarization of the neurons expressing these opsins, thereby exerting an inhibitory effect.