Anatomical and clinical implications of vagal modulation of the spleen

•The vagus nerve controls inflammation and organ injury by regulating the production of inflammatory factors in the spleen.•Most studies showed absence of neurogenic cholinergic markers in the spleen.•Recent studies suggest that vagal regulation of inflammation is mediated by multi-synaptic interactions between the vagus and the splanchnic nerves.•These mechanisms are allowing the design of novel therapeutic strategies for infectious and inflammatory disorders. The vagus nerve coordinates most physiologic functions including the cardiovascular and immune systems. This mechanism has significant clinical implications because electrical stimulation of the vagus nerve can control inflammation and organ injury in infectious and inflammatory disorders. The complex mechanisms that mediate vagal modulation of systemic inflammation are mainly regulated via the spleen. More specifically, vagal stimulation prevents organ injury and systemic inflammation by inhibiting the production of cytokines in the spleen. However, the neuronal regulation of the spleen is controversial suggesting that it can be mediated by either monosynaptic innervation of the splenic parenchyma or secondary neurons from the celiac ganglion depending on the experimental conditions. Recent physiologic and anatomic studies suggest that inflammation is regulated by neuro-immune multi-synaptic interactions between the vagus and the splanchnic nerves to modulate the spleen. Here, we review the current knowledge on these interactions, and discuss their experimental and clinical implications in infectious and inflammatory disorders.