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 3

Morris water maze at 9 weeks after infection.

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Morris water maze at 9 weeks after infection. Mice were infected with S....
Mice were infected with S. pneumoniae and allowed to recover for 2 weeks. At this time, the Morris water maze was assessed. Then, at 9 weeks after infection, the Morris water maze was assessed again in a different pool and different room. (A) Path length during the learning days. (B) Percentage of distance spent in the target quadrant on the fourth day when platform was removed to assess memory strength in mice. Data in A and B represent mean ± SEM of n = 10 in control and n = 8 in S. pneumoniae recovered from infection. *P < 0.05 vs. control mice, unpaired 2-tailed t test. Hippocampus but not amygdala function is altered in mice recovered from S. pneumoniae infection. Mice were infected with S. pneumoniae for 18 weeks, and, at this time, the behavioral tests were conducted. (C) Immediate shock deficit contextual freezing. (D) Cued fear conditioning data in C and D represent mean ± SEM of n = 10 in control and n = 8 in S. pneumoniae–infected mice. **P < 0.01 vs. control mice, 2-way ANOVA followed by Sidak’s multiple comparisons test. MRI brain images of mice recovered from S. pneumoniae infection. (E) Representative multislice images of a mouse brain after recovery from S. pneumoniae infection at 18 weeks after infection. (F) Hippocampus volume was assessed by analyzing voxel based segmentation of the MRI stacks. Data represent mean ± SEM of n = 3. Effects of S. pneumoniae on blood-brain barrier permeability. Mice were treated with S. pneumoniae for 24 hours, and, at this time, permeability was assessed with Evans Direct Blue. (G) Quantification of brain permeability. Data represent mean ± SEM of n = 3. **P < 0.01 vs. control mice, 1-way ANOVA followed by Tukey’s multiple comparisons test. (H) Permeability image in control, B. pertussis toxin– (PTX, used as a positive control for permeability), and S. pneumoniae–infected mice for 24 hours.