Targeting neural reflex circuits in immunity to treat kidney disease

Key Points Neural circuits that control immunity and inflammation provide novel targets for the treatment of kidney disease and hypertension Activation of the cholinergic anti-inflammatory pathway (CAP) blocks splenic-dependent systemic inflammation and acute kidney injury (AKI); non-invasive, nonpharmacological approaches to activate the CAP include ultrasound application and vagus nerve stimulation Neural circuits that directly regulate kidney function or carry sensory feedback from the kidney to the central nervous system could provide additional mechanisms for bidirectional neuroimmunomodulation of kidney disease Interactions between neural circuits and the immune system have important roles in the pathogenesis of hypertension and renal fibrosis Further defining neuroimmunomodulatory pathways in hypertension could enable the development of selective neuronal stimulatory or inhibitory strategies for lowering blood pressure that could potentially be more effective than renal denervation Optogenetic tools provide unprecedented opportunities to dissect the neural pathways that control immunity and inflammation and enable the identification of novel approaches to therapy for kidney diseases In this Review, Mark Okusa and colleagues discuss the role of neural circuits in the control of renal inflammation as well as the therapeutic potential of targeting these circuits in the settings of acute kidney injury, kidney fibrosis and hypertension. Neural pathways regulate immunity and inflammation via the inflammatory reflex and specific molecular targets can be modulated by stimulating neurons. Neuroimmunomodulation by nonpharmacological methods is emerging as a novel therapeutic strategy for inflammatory diseases, including kidney diseases and hypertension. Electrical stimulation of vagus neurons or treatment with pulsed ultrasound activates the cholinergic anti-inflammatory pathway (CAP) and protects mice from acute kidney injury (AKI). Direct innervation of the kidney, by afferent and efferent neurons, might have a role in modulating and responding to inflammation in various diseases, either locally or by providing feedback to regions of the central nervous system that are important in the inflammatory reflex pathway. Increased sympathetic drive to the kidney has a role in the pathogenesis of hypertension, and selective modulation of neuroimmune interactions in the kidney could potentially be more effective for lowering blood pressure and treating inflammatory