Foreign products derived from infecting pathogens and endogenous molecules released from ischemic or ruptured cells converge on the innate immune system, which leads to cytokine release. Tumor necrosis factor (TNF), IL-1, IL-6 and HMGB1 interact with neurons to produce a constellation of signs and symptoms known as ‘sickness behavior’. Because this is the result of cytokines, it is not possible to distinguish between infectious injury and sterile injury as the activating etiology. The nervous system responds to the presence of cytokines and transmits action potentials via the cholinergic anti-inflammatory pathway to downregulate the progression of inflammation. This is a critical gating or controlling step that leads to the resolution of inflammation and prevents further damage. NLR, Nod-like receptor; RIG, retinoic acid inducible gene; Nod, nucleotide-oligomerization domain protein; HMGB1, high-mobility group protein B1.