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CD22 Blockade Alleviates Anesthesia Surgery-Mediated Cognitive Impairment in Aged Mice

ABSTRACT:

Postoperative cognitive dysfunction (POCD) is a common complication characterized by cognitive decline following surgery, with neuroinflammation serving as a critical pathogenic mechanism. Emerging evidence indicates that CD22, an inhibitory receptor primarily expressed on B cells and microglia, plays a key immunomodulatory role in the central nervous system. This study aims to investigate the role of CD22 in mitigating neuroinflammation and ameliorating POCD. Using a murine model of sterile laparotomy, we observed that surgery-induced cognitive impairment was associated with exacerbated hippocampal inflammation and enhanced microglial activation. In contrast, upregulation or agonism of CD22 signaling significantly reduced the release of pro-inflammatory cytokines, including TNF-α and IL-1β, and suppressed microglial overactivation. Notably, CD22-modulated mice exhibited markedly improved performance in behavioral tests assessing learning and memory compared to control groups. Our findings demonstrate that CD22 activation confers protection against POCD by inhibiting surgery-induced neuroinflammation through the S100a9 signaling pathway. Therefore, targeting the CD22 pathway may represent a promising therapeutic strategy for the prevention or treatment of postoperative cognitive dysfunction.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS13028 | MetaboLights | 2025-09-24

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13028_LC-MS_alternating_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13028_LC-MS_alternating_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13028.txt	Txt

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Project description:Background: Current studies provide compelling evidence that the enteric nervous system and neighboring resident macrophages in the muscularis externa modulate neuroimmune processes in the gut after abdominal surgery. While substantial knowledge exists about macrophage-enteric glia interactions, the fate of enteric neurons, which have an indispensable role in gut homeostasis and gastrointestinal motility, has not been thoroughly investigated during enteric neuroinflammation. Therefore, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. Methods: Neuroinflammation and postoperative ileus were induced in various transgenic mice by surgical manipulation of the small intestine. We studied enteric neurons and macrophage-specific transcriptomes using bulk RNA-Seq in neuron-specific RiboTag mice and sorted CX3CR1-GFP+ macrophages. To investigate their intercellular communication, we treated CX3CR1-GFP+ mice with CSFR1-antibody to deplete macrophages and subsequently induce POI through surgical trauma. These mice were examined for gastrointestinal motility, immune cell infiltration, and neuronal function. Ultimately, we validated the murine data in human gut samples collected early and late during abdominal surgery to understand the impact of surgical manipulation on patients' enteric nervous system function. Results: We detected strong neuronal activation in the early postsurgical phase, followed, after 24h, by transcriptional signatures of neuronal proliferation, neuronal death, and synaptic degradation. Neuron-specific transcriptome analysis confirmed these changes and verified the neuronal responses to the inflammatory environment. Simultaneously, our study revealed a neurodegenerative profile in macrophage-specific transcriptomes during POI. Depletion of macrophages before surgical manipulation led to decreased neuronal death, less synaptic decay, and improved GI motility, emphasizing the essential role of macrophages in neurodegeneration during intestinal neuroinflammation. In human jejunal muscularis externa samples, taken at early and late stages of pancreatectomies, we detected reactive and dying neurons with dysregulated gene expression of synaptic signaling and neurogenic processes. Conclusion: Surgical trauma and acute intestinal inflammation activate enteric neurons and induce neurodegeneration with severe synaptic decay, predominantly mediated by resident macrophages. Future studies should focus on neuroprotective mechanisms to dampen neurodegeneration and promote faster recovery from postoperative inflammation and motility disturbances.

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CD22 Blockade Alleviates Anesthesia Surgery-Mediated Cognitive Impairment in Aged Mice

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