Advances in combating acute kidney injury (AKI) require novel and innovative approaches to understanding the pathogenesis of AKI. AKI leads to death and in some cases progression to ESRD. There are no FDA approved drugs for the treatment of AKI. An important area of therapeutics - neuroimmunomodulation of disease - is based upon the interaction between the immune system and the nervous system to defend against injury induced by inflammation. Our current proposal is based on the observation that vagus nerve stimulation (VNS) activates the inflammatory reflex pathway, a neuro-immune circuit that is critical in maintaining immunological homeostasis. Vagal afferent fibers that innervate the kidney are hypothesized to immediately transmit neural impulses to C1 neurons in the lower brainstem that then send efferent signals that terminate on the spleen and other organs to block inflammation. Recent advances in neuroscience provide refined tools that will permit disentanglement of neuronal processes that control inflammation and AKI and provide the foundation for therapeutics. Aim 1 will test the hypothesis that selective afferent and efferent VNS mediate kidney protection by distinct neuronal pathways. Aim 2 will begin unraveling the central circuitry that mediates the protective anti-inflammatory reflexes elicited by afferent VNS by testing whether C1 neurons are the central node linking the afferent and efferent limbs of the inflammatory reflex pathway. The role of C1 neurons, a group of lower brainstem catecholaminergic/glutamatergic neurons, in the inflammatory reflex pathway and protection from AKI will be the main focus of our studies in this aim. C1 neurons regulate both sympathetic and parasympathetic efferents, and we have previously showed that stimulating C1 neurons also protects mice against AKI. Aim 3 will focus on the effector mechanism of efferent VNS. Here we hypothesize that efferent VNS activates α7nAChR expressed on IgM-anti-leukocyte auto-antibody (ALA)-producing B1 lymphocytes, which are critical to block inflammation and AKI. Lastly, we will obtain plasma samples from a completed study of 24 human subjects exposed to VNS to determine if VNS (suppresses proinflammatory cytokines - focus of the original study) increases plasma levels of IgM-ALA (focus of the current study). The proposed studies will be conducted using optogenetics and pharmacogenetics because these approaches offer unprecedented capability to define specific neural circuits that control immunity and inflammation. These studies leverage a multidisciplinary team consisting of nephrologists, neuroscientists and immunologists that seek to define a road map of the underlying inflammatory reflex pathway that protects kidneys from IRI. Attaining genetic and molecular understanding that underlies the diversity of the vagus nerve pathways controlling inflammation is imperative for the future of precision bioelectronic medicine.