Neuroinflammation after surgery: from mechanisms to therapeutic targets

Abstract

Injury is a key driver of inflammation, a critical yet necessary response involving several mediators that is aimed at restoring tissue homeostasis. Inflammation in the central nervous system can be triggered by a variety of stimuli, some intrinsic to the brain and others arising from peripheral signals. Fine-tuned regulation of this response is crucial in a system that is vulnerable due to, for example, aging and ongoing neurodegeneration. In this context, seemingly harmless interventions like a common surgery to repair a broken limb can overwhelm the immune system and become the driver of further complications such as delirium and other perioperative neurocognitive disorders. Here, we discuss potential mechanisms by which the immune system affects the central nervous system after surgical trauma. Together, these neuroimmune interactions are becoming hallmarks of and potential therapeutic targets for multiple neurologic conditions, including those affecting the perioperative space.

Fig. 1 |. Innate immune response to sterile surgical trauma.

Aseptic surgical trauma triggers acute inflammation by inducing inflammatory cytokines and DAMPs. This inflammatory milieu contributes to the recruitment of immune cells at the site of injury, for example, the tibia following intramedullary pinning and fixation, but also affects functions in other organs, including the brain. Monocyte activation is one of the drivers for postoperative neuroinflammation, as found in both preclinical and clinical PND studies. Key PRRs expressed on the surface of monocytes have been implicated in this signaling. HMGB1 binds to TLR4 and RAGE to activate NF-κB, which further transcribes de novo cytokines. This process can synergize with the activation of the NLRP3 inflammasome complex to further elevate the production of IL-1. Plasma and CSF levels of IL-1β have been described in individuals with PNDs. IL-1 induces expression of MCP-1 and facilitates access of CCR2⁺ monocytes in the CNS, possibly contributing to a feed-forward loop leading to non-resolving inflammation and neurologic pathology. NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.

Fig. 2 |. Neuro–immune interactions in the brain after peripheral trauma.

The proinflammatory surgical milieu (including cytokines, chemokines, DAMPs, coagulation factors, immunocytes, and so on) impacts the BBB, thus contributing to ensuing CNS pathology. Microglia, as first responders to changes in the CNS microenvironment, sense the changes following endothelial and BBB openings. Orthopedic surgery causes complement signaling activation in the brain and the deposition of fibrin(ogen) in the hippocampal brain parenchyma. Fibrin(ogen) and complement factors (such as activated forms of C3) are potent activators of microglia via CD11b signaling. reactive microglia release proinflammatory factors, which further contribute to neuroinflammation. In particular, microglia can activate A1 astrocytes via IL-1, C1q and TNF to impact synapses and overall neuronal plasticity. Notably, the increased C3 in A1 astrocytes may in turn contribute to the microglial activation via C3aR. Surgery may also contribute to a DAM-like state, which requires further characterization in various preclinical models. Notably, sTREM2 is elevated in the CSF of patients with delirium after hip fracture, suggesting surgery impacts homeostatic DAM genes and microglial activity following surgical trauma.