Abstract
Perioperative neurocognitive disorders have been widely recognized as common adverse events after surgical intervention. Aging is one of the most important independent risk factors for worsened cognitive outcome, and this deterioration is linked to exacerbated microglia‐mediated neuroinflammation in the aged brain. Under pathological stimulation, microglia are capable of polarizing toward proinflammatory M1 and anti‐inflammatory M2 phenotypes. In the present study, we examined how aging affects microglial responses and neuroinflammation following peripheral surgery. Adult (2‐3 months) and aged (18 months old) male C57/BL6 mice were subjected to tibial fracture or sham surgery. Aged mice exhibited higher level of tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) in the hippocampus. The expression of synaptic protein synaptophysin (SYP) was also markedly reduced in the aged brain after the surgery. Both adult and aged mice showed significant increases in M1 microglial polarization (CD16/32). In contrast, tibial fracture surgery induced a decreased M2 microglial polarization (CD206, Ym1/2, Arg1) in aged brain but enhanced M2 microglial polarization in adult brain. Aged mice have upregulated voltage‐gated proton channel (Hv1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression compared with adult mice. The percentage of CD16/32‐positive M1 microglia colabeling with Hv1 was higher in aged mice after tibial fracture surgery. Thus, Hv1/NADPH oxidase upregulation in the aged brain may shift the dynamic equilibrium of microglial activation toward M1 polarization and exaggerate postoperative neuroinflammatory responses after peripheral surgical intervention.
Highlights
Microglia-mediated neuroinflammation plays a pivotal role in the pathogenesis of Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD).[22]
Functional inhibition of IL-1β, both in mice pretreated with IL-1 receptor antagonist and in IL-1R knockout mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction.[20]
Further study showed that tumor necrosis factor-α (TNF-α) acts upstream of IL-1β and provokes its production in the brain.[23]
Summary
Abbreviations: Arg[1], Arginase 1; CNS, central nervous system; DAPI, 4′,6-diamidino-2-phenylindole; dMCAO, distal middle cerebral artery occlusion; Iba[1], ionized calcium-binding adapter molecule-1; IL-1β, interleukin-1β; iNOS, inducible nitric oxide synthase; MBP, myelin basic protein; NADPH, nicotinamide adenine dinucleotide phosphate; PBS, phosphate-buffered saline; PFA, paraformaldehyde; POCD, postoperative cognitive dysfunction; POD, postoperative delirium; PVDF, polyvinylidene fluoride; RIPA, radioimmunoprecipitation assay; SYP, synaptophysin; TBI, traumatic brain injury; TNF-α, tumor necrosis factor-α
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