Neuroimmunological cross–talk in critical illness

There is evidence that systemic inflammation can propagate to the brain and induce profound changes in brain functions that culminate in delirium. Our understanding of how events originating in the peripheral immune system can ultimately impact on the brain has benefited from the discovery that cytokines and their receptors are expressed in the brain. Furthermore, it is now known that peripherally produced cytokines induce the expression of brain cytokines by brain myeloid cells, including perivascular macrophages and microglia. The brain is therefore able to form a cellular and molecular representation of the peripheral inflammatory response and this occurs in the absence of a breakdown of the blood–brain barrier. Activation of immune-to-brain communication pathways is at the origin of the central components of the host response to infection, including fever, activation of the hypothalamic-pituitary-adrenal axis, and sickness behavior. Communication pathways from the innate immune system to the brain involve the sensory nerves that innervate the site of the body in which the inflammatory response is taking place. Sickness behavior is the normal response of the host to an infection just like fear is an adaptive response to a danger. In addition to their pivotal role in the elicitation of sickness behavior, brain cytokines are also involved in the regulation of learning and memory. Their overexpression during peripheral inflammation is responsible for cognitive dysfunction and alterations in hippocampus-dependent memory. Inflammation is also associated with alterations in mood that can culminate in the development of symptoms of depression. Pro-inflammatory cytokines activate the tryptophan-degrading enzyme indoleamine 2,3 dioxygenase. This results in the formation of kynurenine metabolites, some of which are neurotoxic and can contribute to inflammation-associated depression and cognitive dysfunction. Understanding the way immune-to-brain communication pathways are recruited during surgery and infection should help not only to better understand the pathophysiology of delirium in the intensive care unit (ICU) but also to propose appropriate therapeutic means to prevent or treat postoperative delirium.