Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment
Graciela Andonegui, Erin L. Zelinski, Courtney L. Schubert, Derrice Knight, Laura A. Craig, Brent W. Winston, Simon C. Spanswick, Björn Petri, Craig N. Jenne, Janice C. Sutherland, Rita Nguyen, Natalie Jayawardena, Margaret M. Kelly, Christopher J. Doig, Robert J. Sutherland, Paul Kubes
Graciela Andonegui, Erin L. Zelinski, Courtney L. Schubert, Derrice Knight, Laura A. Craig, Brent W. Winston, Simon C. Spanswick, Björn Petri, Craig N. Jenne, Janice C. Sutherland, Rita Nguyen, Natalie Jayawardena, Margaret M. Kelly, Christopher J. Doig, Robert J. Sutherland, Paul Kubes
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Research Article Inflammation Neuroscience

Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment

Abstract

Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12–18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery–standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments.

Authors

Graciela Andonegui, Erin L. Zelinski, Courtney L. Schubert, Derrice Knight, Laura A. Craig, Brent W. Winston, Simon C. Spanswick, Björn Petri, Craig N. Jenne, Janice C. Sutherland, Rita Nguyen, Natalie Jayawardena, Margaret M. Kelly, Christopher J. Doig, Robert J. Sutherland, Paul Kubes

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Figure 4

S. pneumoniae–infected mice have increased neutrophil recruitment into the brain.

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S. pneumoniae–infected mice have increased neutrophil recruitment into ...
Mice were infected with S. pneumoniae for 24 hours. (A) Intravital microscopy image of the brain vasculature of control mice. Scale bar: 20 μm. (B) Intravital microscopy image of the brain vasculature in S. pneumoniae–infected mice at 24 hours after infection. Neutrophils are visualized in blue, labeled with anti-Ly6G mAb (clone 1A8). Endothelium is visualized in red, labeled with anti-CD31 mAb. Scale bar: 20 μm. (C) Quantification of neutrophil rolling flux (n = 5). (D) Quantification of neutrophil adhesion (n = 5). Data in C and D represent mean ± SEM. ***P < 0.001 vs. control, unpaired 2-tailed t test. (E) Coronal brain section image showing adherent neutrophils in the inset (arrows showing neutrophils visualized in blue). Neutrophils were labeled with anti-Ly6G mAb (clone 1A8) and endothelium was labeled with anti-CD31 mAb. (F) Quantification of neutrophil adhesion in coronal sections at 4 hours (S. pneumoniae 4h) or 24 hours (S. pneumoniae 24h) after S. pneumoniae infection (n = 3 ). Data represent mean ± SEM. *P < 0.05 vs. control, 1-way ANOVA followed by Dunnett’s multiple comparisons test.