Recognition of microbial products and alarmins to induce systemic inflammation and impacts on the brain. Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs or alarmins) induce systemic inflammatory mediators in multiple tissues of the body after infection, surgery, injury or arthritis. Although some aspects of the pathways shown remain unclear, it is clear that all conditions can bring about elevated systemic inflammatory mediators and that these can signal to the brain via well established routes, including direct neural activation via afferent nerves and activation of inflammatory cells in circumventricular organs lacking a patent blood–brain barrier, allowing secretion of inflammatory mediators into the brain parenchyma and activation of soluble mediators at the brain endothelium. Direct impacts on brain pathology or on cognitive function have been shown for all of these insults. Dashed arrows indicate that though these mediators are the result of inflammatory stimulation in the tissues/joints, they also contribute to the ongoing inflammation in those tissues. HMGB1, high mobility group box-1; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; NO, nitric oxide; PGN, peptidoglycan; ROS, reactive oxygen species; TNF, tumour necrosis factor.