Journal Article

Cecal Ligation and Puncture Results in Long-Term Central Nervous System Myeloid Inflammation

Parent, Jack M., Cooke, Christopher L., Standiford, Theodore J., Thompson, Robert C., Ghantasala, Ramya, Newstead, Michael W., Singer, Kanakadurga, Singer, Benjamin H., Zeng, Xianying, Murphy, Geoffrey G., Iwashyna, Theodore J.

2016

Overview

Survivors of sepsis often experience long-term cognitive and functional decline. Previous studies utilizing lipopolysaccharide injection and cecal ligation and puncture in rodent models of sepsis have demonstrated changes in depressive-like behavior and learning and memory after sepsis, as well as evidence of myeloid inflammation and cytokine expression in the brain, but the long-term course of neuroinflammation after sepsis remains unclear. Here, we utilize cecal ligation and puncture with greater than 80% survival as a model of sepsis. We found that sepsis survivor mice demonstrate deficits in extinction of conditioned fear, but no acquisition of fear conditioning, nearly two months after sepsis. These cognitive changes occur in the absence of neuronal loss or changes in synaptic density in the hippocampus. Sepsis also resulted in infiltration of monocytes and neutrophils into the CNS at least two weeks after sepsis in a CCR2 independent manner. Cellular inflammation is accompanied by long-term expression of pro-inflammatory cytokine and chemokine genes, including TNFα and CCR2 ligands, in whole brain homogenates. Gene expression analysis of microglia revealed that while microglia do express anti-microbial genes and damage-associated molecular pattern molecules of the S100A family of genes at least 2 weeks after sepsis, they do not express the cytokines observed in whole brain homogenates. Our results indicate that in a naturalistic model of infection, sepsis results in long-term neuroinflammation, and that this sustained inflammation is likely due to interactions among multiple cell types, including resident microglia and peripherally derived myeloid cells.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animal models / Animals / Antiinfectives and antibacterials / Biology and Life Sciences / Blood-brain barrier / Brain / Brain - metabolism / Brain - pathology / Care and treatment / CCR2 protein / Cecum / Cecum - physiopathology / Cell Separation / Central nervous system / Central Nervous System - immunology / Central Nervous System - pathology / Chemokines / Cognitive ability / Conditioning / Conditioning (Psychology) / Critical care / Cytokines / Cytokines - metabolism / Damage patterns / Dendritic Spines - pathology / Development and progression / Disease Models, Animal / Drug dosages / Fear / Fear conditioning / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Genes / Golgi Apparatus - metabolism / Hippocampus - metabolism / Infections / Infiltration / Inflammation / Inflammation - pathology / Internal medicine / Learning / Leukocytes (neutrophilic) / Ligands / Ligation / Lipopolysaccharides / Lipopolysaccharides - chemistry / Male / Medical schools / Medicine / Medicine and Health Sciences / Memory / Mice / Mice, Inbred C57BL / Microglia / Microorganisms / Monocyte chemoattractant protein 1 / Monocytes / Monocytes - cytology / Mood disorders / Myeloid cells / Nervous system / Neurosciences / Neutrophils - cytology / Permeability / Punctures / Residential density / Rodents / Sepsis / Sepsis - physiopathology / Survival / Synaptic density / Tumor necrosis factor-TNF / Tumor necrosis factor-α