Delirium is a frequently occurring clinical syndrome that is associated with cognitive decline. We hypothesise that poor outcome after delirium is caused by neuroinflammation and that microglia, the brain’s innate immune cells, play a pivotal role. In this thesis, we studied the pathogenesis of the neuroinflammatory response to peripheral, infectious insults, focussing on microglial cells and inflammatory mediators. The first part addresses the pathophysiology of neuroinflammation in rodents. In pursuit of a clinically relevant model to induce microglia activation, we developed an abdominal infection model with live bacteria activation (chapter 2). In older infected mice, we observed increases in microglial cell numbers and inflammatory mediators as compared to young infected mice (chapter 3). In the second part we assessed cerebrospinal fluid (CSF) of older patients who received surgery for a hip fracture, and are therefore at risk for delirium. We found a dysregulation of immune mediators in preoperative CSF of patients who developed a postoperative delirium (chapters 4 and 5). The last part reports on neuropathology of patients with systemic inflammation. Brain tissue of patients who died of septic shock had localized and strong upregulation of microglia in comparison to patients who died of other, non-inflammatory causes (chapter 6). Finally we present a narrative review on brain histopathology of sepsis patients (chapter 7). To conclude, we consistently found an upregulation of inflammation markers, which was most pronounced in older and more severely affected individuals.