Erythropoietin Attenuates Postoperative Cognitive Dysfunction by Shifting Macrophage Activation toward the M2 Phenotype.

Jae Hoon Lee,So Yeon Kim,Eun Jung Kim,Ji-Hyun Jeong,Bon-Nyeo Koo,Eun Hee Kam,So Yeong Cheon,Seungsoo Chung

doi:10.3389/fphar.2017.00839

Jae Hoon Lee, So Yeon Kim + Show 6 more

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https://doi.org/10.3389/fphar.2017.00839

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Abstract

Postoperative cognitive dysfunction (POCD) may be driven by transference of the innate immune response to the brain after aseptic surgical damage. Macrophages are key mediators of innate immunity that can display a pro-inflammatory M1 phenotype or an anti-inflammatory M2 phenotype. Erythropoietin (EPO) is a hematopoietic hormone that exerts anti-inflammatory effects by influencing macrophage function. We hypothesized that EPO would prevent POCD by promoting macrophage phenotype switching to the M2 phenotype post-surgery. To evaluate the effects of EPO on POCD and macrophage polarization post-surgery, we administered EPO (5,000 U/kg) with or without an arginase inhibitor (amino-6-boronohexanoic acid, 10 mg/kg) to ICR mice before and after abdominal surgery. Forty-eight hours post-surgery, we assessed memory, synapse function, and macrophage/microglial phenotypes in the spleen and hippocampus. We also investigated M1/M2 phenotypes in RAW264.7 and BV2 cells stimulated with lipopolysaccharide and interferon-γ (M1 inducers) in the presence or absence of EPO. EPO prevented POCD, decreased surgery-related synaptic dysfunction, and attenuated pro-inflammatory cytokine generation in the hippocampus. Moreover, EPO suppressed M1-related genes expression and promoted M2 genes expression in the spleen and hippocampus post-surgery. Furthermore, EPO decreased the proportions of macrophages/microglia expressing an M1 surface marker (CD40) and increased those expressing an M2 surface marker (CD206). Arginase inhibition abolished the beneficial effects of EPO on POCD. In vitro, EPO treatment promoted switching of RAW264.7 and BV2 cells stimulated with M1 inducers to an M2 phenotype. In conclusion, EPO prevents POCD by promoting macrophage phenotype switching toward the M2 phenotype.

Highlights

Postoperative cognitive dysfunction (POCD) is a major neurological complication after surgery that adversely affects the quality of life, social independence, and mortality of patients (Steinmetz et al, 2009; Mashour et al, 2015)
Erythropoietin and Postoperative Cognitive Decline have been associated with the development of POCD, mounting preclinical evidence suggests that inflammation in the brain induced by systemic inflammation after surgery is a core pathogenic factor (Cibelli et al, 2010; Terrando et al, 2010; Hovens et al, 2014; Vacas et al, 2014)
For evaluations of learning and memory, there were significant between-group differences in the latency times in the passive avoidance test (Figure 1B, P = 0.006), and the duration spent exploring the novel object in the novel object recognition test (Figure 1C, P < 0.001)

Summary

Introduction

Postoperative cognitive dysfunction (POCD) is a major neurological complication after surgery that adversely affects the quality of life, social independence, and mortality of patients (Steinmetz et al, 2009; Mashour et al, 2015). Erythropoietin and Postoperative Cognitive Decline have been associated with the development of POCD, mounting preclinical evidence suggests that inflammation in the brain (neuroinflammation) induced by systemic inflammation after surgery is a core pathogenic factor (Cibelli et al, 2010; Terrando et al, 2010; Hovens et al, 2014; Vacas et al, 2014). The resulting increase in pro-inflammatory cytokine expression, especially within hippocampus, eventually leads to cognitive dysfunction (Wan et al, 2007; Dilger and Johnson, 2008; Terrando et al, 2011; Degos et al, 2013). There is little evidence regarding the association between POCD and patterns of macrophage activation

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