Impact on the brain of the inflammatory response to surgery

Abstract

The brain is both the orchestrator as well as the target of the innate immune system's response to the aseptic trauma of surgery. When trauma-induced inflammation is not appropriately regulated persistent neuro-inflammation interferes with the synaptic plasticity that underlies the learning and memory aspects of cognition. The complications that ensue, include postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) at two poles of a constellation that is now termed perioperative neurocognitive disorders. While the relationship of acute POD to the more indolent POCD is not completely understood both can be further complicated by earlier-onset of dementia and higher mortality. How and why these disorders occur is the focus of this report. The innate immune system response to peripheral trauma signals to the brain through a regulated cascade of cellular and molecular actors producing a teleological defense mechanism, "sickness behavior," to curtail further injury and initiate repair. Sickness behavior, including disordered cognition, is terminated by neural and humoral pathways that restore homeostasis and launch the organism on a path to good health. With so many "moving parts" the innate immune system is vulnerable in clinical settings that include advanced age and lifestyle-induced diseases such as "unhealthy" obesity and the inevitable insulin resistance. Under these conditions, inflammation may become exaggerated and long-lived. Consideration is provided how to identify the high-risk surgical patient and both pharmacological (including biological compounds) and non-pharmacological strategies to customize care.

Conflict of interest statement

Conflict of Interest:

The authors report no Conflicts of Interest.

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Figures

Figure 1:

Following peripheral trauma (indicated by the red intramedullary nail in a tibia that has been fractured), high molecular group box protein 1 (HMGB1) is passively released. This damage-associated molecular pattern (DAMP) binds to pattern recognition receptors (PRR) on circulating bone marrow-derived monocytes (BM-DMs) that signal to activate NF-κB, a transcription factor that passes into the nucleus to cause increase expression and release of pro-inflammatory cytokines that are capable of disrupting the blood brain barrier. Within the brain parenchyma the chemokine MCP-1 (also referred to as CCL2) is upregulated and attracts the BM-DMs through binding to its cognate receptor, CCR2. In the presence of translocated CCR2-expressing BM-DMs as well as through other direct and indirect mechanisms the resident quiescent microglia become activated. Together, the BM-DMs and activate microglia release HMGB1(a feed-forward mechanism) and pro- inflammatory cytokines that disrupt long-term potentiation (LTP) thereby blocking synaptic plasticity changes that are required for the cognitive functions of learning and memory.