Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability

• Cytokines display a direct neuromodulatory role in CNS and PNS.
• Cytokines modulate VGC and ROC and presynaptic neurotransmitter release.
• Cytokines affect neuronal excitability also indirectly by activating glial cells.
• Cytokines have a physiological role in synaptic transmission and plasticity.
• Excessive cell exposure to cytokines may mediate neuropathologic effects.

Increasing evidence underlines that prototypical inflammatory cytokines (IL-1β, TNF-α and IL-6) either synthesized in the central (CNS) or peripheral nervous system (PNS) by resident cells, or imported by immune blood cells, are involved in several pathophysiological functions, including an unexpected impact on synaptic transmission and neuronal excitability.This review describes these unconventional neuromodulatory properties of cytokines, that are distinct from their classical action as effector molecules of the immune system. In addition to the role of cytokines in brain physiology, we report evidence that dysregulation of their biosynthesis and cellular release, or alterations in receptor-mediated intracellular pathways in target cells, leads to neuronal cell dysfunction and modifications in neuronal network excitability. As a consequence, targeting of these cytokines, and related signalling molecules, is considered a novel option for the development of therapies in various CNS or PNS disorders associated with an inflammatory component.This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’.