Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner

Abstract

Background: The pathophysiological mechanisms underlying postoperative cognitive dysfunction (POCD) remain unclear over the years. Neuroinflammation caused by surgery has been recognized as an important element in the development of POCD. Many studies also suggest that the vagus nerve plays an important role in transmitting peripheral injury signals to the central nervous system (CNS) and the resultant neuroinflammation. Previously, we have demonstrated that brain mast cells (BMCs), as the “first responders”, play a vital role in neuroinflammation and POCD. However, how the vagus nerve communicates with BMCs in POCD has not yet been clarified.Methods: In the current study, we highlighted the role of the vagus nerve as a conduction highway in surgery-induced neuroinflammation for the first time. In our model, we tested if mice underwent unilateral cervical vagotomy (VGX) had less neuroinflammation compared to the shams after laparotomy (LP) at an early stage. To further investigate the roles of mast cells and glutamate in the process, we employed KitW-sh mice and primary bone marrow-derived MCs to verify the glutamate-NR2B axis on MCs once again.Results: Our results demonstrated that there were higher levels of glutamate and BMCs activation as early as 4 h after LP. Meanwhile, vagotomy could partially block the increases and reduce neuroinflammation caused by peripheral inflammation during the acute phase. Excitingly, inhibition of NR2B receptor and knockout of mast cells can attenuateneuroinflammation induced by glutamate.Conclusion: Taken together, our findings indicate that the vagus is a high-speed pathway in the transmission of peripheral inflammation to the CNS. Activation of BMCs triggered a neuroinflammatory cascade. Inhibition of NR2B receptor on BMCs can reduce glutamate-induced BMCs activation, neuroinflammation, and memory impairment, suggesting a novel treatment strategy for POCD.

Assessment of nucleus accumbens impairment in a rat model of postoperative cognitive dysfunction using diffusion tensor imaging

“…However, several studies show that neuroinflammation is an important mechanism in POCD and depression. 11,12 Activation astrocytes secrete antiinflammatory mediators, which help to resolve the injury and prevent further damage. 29,30 Previous studies have shown that inflammation can trigger depression.…”

“…The mechanism of POCD is still not clear. However, several studies show that neuroinflammation is an important mechanism in POCD and depression 11,12 . Activation astrocytes secrete anti‐inflammatory mediators, which help to resolve the injury and prevent further damage 29,30 .…”

“…10 There are various mechanisms of POCD, among which neuroinflammation is one of the main causes of memory decline and behavioural disorders. 11,12 Inflammatory mediators often activate astrocytes, and the irreversible injury of astrocytes may aggravate cerebral ischaemia and lead to POCD in the elderly. 13 At the same time, activated astrocytes in the ageing brain produce cell fibrosis through accumulation of intermediate filaments of glycogen and glial fibrillary protein (GFAP), which is a key cause of ultimate cell dysfunction.…”

“…There are various mechanisms of POCD, among which neuroinflammation is one of the main causes of memory decline and behavioural disorders 11,12 . Inflammatory mediators often activate astrocytes, and the irreversible injury of astrocytes may aggravate cerebral ischaemia and lead to POCD in the elderly 13 .…”

Activation of Mast Cells by Neuropeptides: The Role of Pro-inflammatory and Anti-Inflammatory Cytokines

“…Vasodilation, mast cell activation Some CNS diseases can lead to an increase in the expression of CRH-1 receptor in MCs (87), with an elevation of CRH levels and the generation of neurological disorders. In some neurological disorders, there may be an increase in MCs expressing the CRH-1 receptor with induction of inflammation (88).…”